Identification of anticancer drugs to radiosensitise BRAF-wild-type and mutant colorectal cancer
Identifieur interne : 000439 ( Pmc/Corpus ); précédent : 000438; suivant : 000440Identification of anticancer drugs to radiosensitise BRAF-wild-type and mutant colorectal cancer
Auteurs : Rebecca Carter ; Azadeh Cheraghchi-Bashi ; Adam Westhorpe ; Sheng Yu ; Yasmin Shanneik ; Elena Seraia ; Djamila Ouaret ; Yasuhiro Inoue ; Catherine Koch ; Jenny Wilding ; Daniel Ebner ; Anderson J. Ryan ; Francesca M. Buffa ; Ricky A. SharmaSource :
- Cancer Biology & Medicine [ 2095-3941 ] ; 2019.
Abstract
Patients with
We screened 298 oncological drugs with and without ionising radiation in colorectal cancer cells isogenic for
Most consistently identified hits were drugs targeting cell growth/proliferation or DNA damage repair. The most effective class of drugs that radiosensitised wild-type and mutant cell lines was PARP inhibitors. In clonogenic survival assays, talazoparib produced a radiation enhancement ratio of 1.9 in DLD1 (
Our method for screening large drug libraries for radiosensitisation has identified PARP inhibitors as promising radiosensitisers of colorectal cancer cells with wild-type and mutant
Url:
DOI: 10.20892/j.issn.2095-3941.2018.0284
PubMed: 31516745
PubMed Central: 6713640
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PMC:6713640Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Identification of anticancer drugs to radiosensitise <italic>BRAF</italic>-wild-type and mutant colorectal cancer
</title><author><name sortKey="Carter, Rebecca" sort="Carter, Rebecca" uniqKey="Carter R" first="Rebecca" last="Carter">Rebecca Carter</name><affiliation><nlm:aff id="aff1"><addr-line>NIHR University College London Hospitals Biomedical Research Centre, UCL Cancer Institute, University College London, London WC1E 6DD, UK</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><addr-line>NIHR Oxford Biomedical Research Centre, Department of Oncology, University of Oxford, Oxford OX1 2JD, UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cheraghchi Bashi, Azadeh" sort="Cheraghchi Bashi, Azadeh" uniqKey="Cheraghchi Bashi A" first="Azadeh" last="Cheraghchi-Bashi">Azadeh Cheraghchi-Bashi</name><affiliation><nlm:aff id="aff2"><addr-line>NIHR Oxford Biomedical Research Centre, Department of Oncology, University of Oxford, Oxford OX1 2JD, UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Westhorpe, Adam" sort="Westhorpe, Adam" uniqKey="Westhorpe A" first="Adam" last="Westhorpe">Adam Westhorpe</name><affiliation><nlm:aff id="aff1"><addr-line>NIHR University College London Hospitals Biomedical Research Centre, UCL Cancer Institute, University College London, London WC1E 6DD, UK</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><addr-line>NIHR Oxford Biomedical Research Centre, Department of Oncology, University of Oxford, Oxford OX1 2JD, UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Yu, Sheng" sort="Yu, Sheng" uniqKey="Yu S" first="Sheng" last="Yu">Sheng Yu</name><affiliation><nlm:aff id="aff3"><addr-line>Computational Biology and Integrative Genomics, University of Oxford, Oxford OX1 2JD, UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Shanneik, Yasmin" sort="Shanneik, Yasmin" uniqKey="Shanneik Y" first="Yasmin" last="Shanneik">Yasmin Shanneik</name><affiliation><nlm:aff id="aff2"><addr-line>NIHR Oxford Biomedical Research Centre, Department of Oncology, University of Oxford, Oxford OX1 2JD, UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Seraia, Elena" sort="Seraia, Elena" uniqKey="Seraia E" first="Elena" last="Seraia">Elena Seraia</name><affiliation><nlm:aff id="aff4"><addr-line>NDM Research Building, Nuffield Department of Medicine, University of Oxford, Oxford OX1 2JD, UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ouaret, Djamila" sort="Ouaret, Djamila" uniqKey="Ouaret D" first="Djamila" last="Ouaret">Djamila Ouaret</name><affiliation><nlm:aff id="aff5"><addr-line>Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX1 2JD, UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Inoue, Yasuhiro" sort="Inoue, Yasuhiro" uniqKey="Inoue Y" first="Yasuhiro" last="Inoue">Yasuhiro Inoue</name><affiliation><nlm:aff id="aff6"><addr-line>Mie University, Graduate School of Medicine, Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Edobashi 2-174, Tsu, Japan</addr-line></nlm:aff></affiliation></author><author><name sortKey="Koch, Catherine" sort="Koch, Catherine" uniqKey="Koch C" first="Catherine" last="Koch">Catherine Koch</name><affiliation><nlm:aff id="aff7"><addr-line>Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA</addr-line></nlm:aff></affiliation></author><author><name sortKey="Wilding, Jenny" sort="Wilding, Jenny" uniqKey="Wilding J" first="Jenny" last="Wilding">Jenny Wilding</name><affiliation><nlm:aff id="aff5"><addr-line>Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX1 2JD, UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ebner, Daniel" sort="Ebner, Daniel" uniqKey="Ebner D" first="Daniel" last="Ebner">Daniel Ebner</name><affiliation><nlm:aff id="aff8"><addr-line>Target Discovery Institute, National Phenotypic Screening Centre, Nuffield Department of Medicine, University of Oxford, Oxford OX1 2JD, UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ryan, Anderson J" sort="Ryan, Anderson J" uniqKey="Ryan A" first="Anderson J." last="Ryan">Anderson J. Ryan</name><affiliation><nlm:aff id="aff9"><addr-line>CRUK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX1 2JD, UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Buffa, Francesca M" sort="Buffa, Francesca M" uniqKey="Buffa F" first="Francesca M." last="Buffa">Francesca M. Buffa</name><affiliation><nlm:aff id="aff9"><addr-line>CRUK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX1 2JD, UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sharma, Ricky A" sort="Sharma, Ricky A" uniqKey="Sharma R" first="Ricky A." last="Sharma">Ricky A. Sharma</name><affiliation><nlm:aff id="aff1"><addr-line>NIHR University College London Hospitals Biomedical Research Centre, UCL Cancer Institute, University College London, London WC1E 6DD, UK</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><addr-line>NIHR Oxford Biomedical Research Centre, Department of Oncology, University of Oxford, Oxford OX1 2JD, UK</addr-line></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31516745</idno><idno type="pmc">6713640</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713640</idno><idno type="RBID">PMC:6713640</idno><idno type="doi">10.20892/j.issn.2095-3941.2018.0284</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000439</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000439</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Identification of anticancer drugs to radiosensitise <italic>BRAF</italic>-wild-type and mutant colorectal cancer
</title><author><name sortKey="Carter, Rebecca" sort="Carter, Rebecca" uniqKey="Carter R" first="Rebecca" last="Carter">Rebecca Carter</name><affiliation><nlm:aff id="aff1"><addr-line>NIHR University College London Hospitals Biomedical Research Centre, UCL Cancer Institute, University College London, London WC1E 6DD, UK</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><addr-line>NIHR Oxford Biomedical Research Centre, Department of Oncology, University of Oxford, Oxford OX1 2JD, UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cheraghchi Bashi, Azadeh" sort="Cheraghchi Bashi, Azadeh" uniqKey="Cheraghchi Bashi A" first="Azadeh" last="Cheraghchi-Bashi">Azadeh Cheraghchi-Bashi</name><affiliation><nlm:aff id="aff2"><addr-line>NIHR Oxford Biomedical Research Centre, Department of Oncology, University of Oxford, Oxford OX1 2JD, UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Westhorpe, Adam" sort="Westhorpe, Adam" uniqKey="Westhorpe A" first="Adam" last="Westhorpe">Adam Westhorpe</name><affiliation><nlm:aff id="aff1"><addr-line>NIHR University College London Hospitals Biomedical Research Centre, UCL Cancer Institute, University College London, London WC1E 6DD, UK</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><addr-line>NIHR Oxford Biomedical Research Centre, Department of Oncology, University of Oxford, Oxford OX1 2JD, UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Yu, Sheng" sort="Yu, Sheng" uniqKey="Yu S" first="Sheng" last="Yu">Sheng Yu</name><affiliation><nlm:aff id="aff3"><addr-line>Computational Biology and Integrative Genomics, University of Oxford, Oxford OX1 2JD, UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Shanneik, Yasmin" sort="Shanneik, Yasmin" uniqKey="Shanneik Y" first="Yasmin" last="Shanneik">Yasmin Shanneik</name><affiliation><nlm:aff id="aff2"><addr-line>NIHR Oxford Biomedical Research Centre, Department of Oncology, University of Oxford, Oxford OX1 2JD, UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Seraia, Elena" sort="Seraia, Elena" uniqKey="Seraia E" first="Elena" last="Seraia">Elena Seraia</name><affiliation><nlm:aff id="aff4"><addr-line>NDM Research Building, Nuffield Department of Medicine, University of Oxford, Oxford OX1 2JD, UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ouaret, Djamila" sort="Ouaret, Djamila" uniqKey="Ouaret D" first="Djamila" last="Ouaret">Djamila Ouaret</name><affiliation><nlm:aff id="aff5"><addr-line>Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX1 2JD, UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Inoue, Yasuhiro" sort="Inoue, Yasuhiro" uniqKey="Inoue Y" first="Yasuhiro" last="Inoue">Yasuhiro Inoue</name><affiliation><nlm:aff id="aff6"><addr-line>Mie University, Graduate School of Medicine, Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Edobashi 2-174, Tsu, Japan</addr-line></nlm:aff></affiliation></author><author><name sortKey="Koch, Catherine" sort="Koch, Catherine" uniqKey="Koch C" first="Catherine" last="Koch">Catherine Koch</name><affiliation><nlm:aff id="aff7"><addr-line>Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA</addr-line></nlm:aff></affiliation></author><author><name sortKey="Wilding, Jenny" sort="Wilding, Jenny" uniqKey="Wilding J" first="Jenny" last="Wilding">Jenny Wilding</name><affiliation><nlm:aff id="aff5"><addr-line>Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX1 2JD, UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ebner, Daniel" sort="Ebner, Daniel" uniqKey="Ebner D" first="Daniel" last="Ebner">Daniel Ebner</name><affiliation><nlm:aff id="aff8"><addr-line>Target Discovery Institute, National Phenotypic Screening Centre, Nuffield Department of Medicine, University of Oxford, Oxford OX1 2JD, UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ryan, Anderson J" sort="Ryan, Anderson J" uniqKey="Ryan A" first="Anderson J." last="Ryan">Anderson J. Ryan</name><affiliation><nlm:aff id="aff9"><addr-line>CRUK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX1 2JD, UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Buffa, Francesca M" sort="Buffa, Francesca M" uniqKey="Buffa F" first="Francesca M." last="Buffa">Francesca M. Buffa</name><affiliation><nlm:aff id="aff9"><addr-line>CRUK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX1 2JD, UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sharma, Ricky A" sort="Sharma, Ricky A" uniqKey="Sharma R" first="Ricky A." last="Sharma">Ricky A. Sharma</name><affiliation><nlm:aff id="aff1"><addr-line>NIHR University College London Hospitals Biomedical Research Centre, UCL Cancer Institute, University College London, London WC1E 6DD, UK</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><addr-line>NIHR Oxford Biomedical Research Centre, Department of Oncology, University of Oxford, Oxford OX1 2JD, UK</addr-line></nlm:aff></affiliation></author></analytic><series><title level="j">Cancer Biology & Medicine</title><idno type="ISSN">2095-3941</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Objective</title><p>Patients with <italic>BRAF</italic>-mutant colorectal cancer (CRC) have a poor prognosis. Molecular status is not currently used to select which drug to use in combination with radiotherapy. Our aim was to identify drugs that radiosensitise CRC cells with known <italic>BRAF</italic> status.
</p></sec><sec><title>Methods</title><p>We screened 298 oncological drugs with and without ionising radiation in colorectal cancer cells isogenic for <italic>BRAF</italic>. Hits from rank product analysis were validated in a 16-cell line panel of human CRC cell lines, using clonogenic survival assays and xenograft models <italic>in vivo</italic>.
</p></sec><sec><title>Results</title><p>Most consistently identified hits were drugs targeting cell growth/proliferation or DNA damage repair. The most effective class of drugs that radiosensitised wild-type and mutant cell lines was PARP inhibitors. In clonogenic survival assays, talazoparib produced a radiation enhancement ratio of 1.9 in DLD1 (<italic>BRAF</italic>-wildtype) cells and 1.8 in RKO (<italic>BRAF</italic> V600E) cells. In DLD1 xenografts, talazoparib significantly increased the inhibitory effect of radiation on tumour growth (<italic>P</italic> ≤ 0.01).
</p></sec><sec><title>Conclusions</title><p>Our method for screening large drug libraries for radiosensitisation has identified PARP inhibitors as promising radiosensitisers of colorectal cancer cells with wild-type and mutant <italic>BRAF</italic> backgrounds.
</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Cancer Biol Med</journal-id><journal-id journal-id-type="iso-abbrev">Cancer Biol Med</journal-id><journal-id journal-id-type="publisher-id">CBM</journal-id><journal-title-group><journal-title>Cancer Biology & Medicine</journal-title></journal-title-group><issn pub-type="ppub">2095-3941</issn><publisher><publisher-name>Chinese Anti-Cancer Association</publisher-name><publisher-loc>Tianjing China</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31516745</article-id><article-id pub-id-type="pmc">6713640</article-id><article-id pub-id-type="publisher-id">cbm-16-2-234</article-id><article-id pub-id-type="doi">10.20892/j.issn.2095-3941.2018.0284</article-id><article-categories><subj-group subj-group-type="heading"><subject>Original Article</subject></subj-group></article-categories><title-group><article-title>Identification of anticancer drugs to radiosensitise <italic>BRAF</italic>-wild-type and mutant colorectal cancer
</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Carter</surname><given-names>Rebecca</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="author-notes" rid="fn1">*</xref></contrib><contrib contrib-type="author"><name><surname>Cheraghchi-Bashi</surname><given-names>Azadeh</given-names></name><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="author-notes" rid="fn1">*</xref></contrib><contrib contrib-type="author"><name><surname>Westhorpe</surname><given-names>Adam</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Yu</surname><given-names>Sheng</given-names></name><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Shanneik</surname><given-names>Yasmin</given-names></name><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Seraia</surname><given-names>Elena</given-names></name><xref ref-type="aff" rid="aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Ouaret</surname><given-names>Djamila</given-names></name><xref ref-type="aff" rid="aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>Inoue</surname><given-names>Yasuhiro</given-names></name><xref ref-type="aff" rid="aff6">6</xref></contrib><contrib contrib-type="author"><name><surname>Koch</surname><given-names>Catherine</given-names></name><xref ref-type="aff" rid="aff7">7</xref></contrib><contrib contrib-type="author"><name><surname>Wilding</surname><given-names>Jenny</given-names></name><xref ref-type="aff" rid="aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>Ebner</surname><given-names>Daniel</given-names></name><xref ref-type="aff" rid="aff8">8</xref></contrib><contrib contrib-type="author"><name><surname>Ryan</surname><given-names>Anderson J.</given-names></name><xref ref-type="aff" rid="aff9">9</xref></contrib><contrib contrib-type="author"><name><surname>Buffa</surname><given-names>Francesca M.</given-names></name><xref ref-type="aff" rid="aff9">9</xref></contrib><contrib contrib-type="author"><name><surname>Sharma</surname><given-names>Ricky A.</given-names></name><xref ref-type="corresp" rid="cor1">*</xref><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref><email>ricky.sharma@ucl.ac.uk</email></contrib></contrib-group><aff id="aff1"><label>1</label><addr-line>NIHR University College London Hospitals Biomedical Research Centre, UCL Cancer Institute, University College London, London WC1E 6DD, UK</addr-line></aff><aff id="aff2"><label>2</label><addr-line>NIHR Oxford Biomedical Research Centre, Department of Oncology, University of Oxford, Oxford OX1 2JD, UK</addr-line></aff><aff id="aff3"><label>3</label><addr-line>Computational Biology and Integrative Genomics, University of Oxford, Oxford OX1 2JD, UK</addr-line></aff><aff id="aff4"><label>4</label><addr-line>NDM Research Building, Nuffield Department of Medicine, University of Oxford, Oxford OX1 2JD, UK</addr-line></aff><aff id="aff5"><label>5</label><addr-line>Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX1 2JD, UK</addr-line></aff><aff id="aff6"><label>6</label><addr-line>Mie University, Graduate School of Medicine, Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Edobashi 2-174, Tsu, Japan</addr-line></aff><aff id="aff7"><label>7</label><addr-line>Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA</addr-line></aff><aff id="aff8"><label>8</label><addr-line>Target Discovery Institute, National Phenotypic Screening Centre, Nuffield Department of Medicine, University of Oxford, Oxford OX1 2JD, UK</addr-line></aff><aff id="aff9"><label>9</label><addr-line>CRUK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX1 2JD, UK</addr-line></aff><author-notes><corresp id="cor1">Ricky Sharma E-mail:
<email>ricky.sharma@ucl.ac.uk</email></corresp><fn id="fn1"><p>*These authors contributed equally to this work.</p></fn></author-notes><pub-date pub-type="ppub"><month>5</month><year>2019</year></pub-date><volume>16</volume><issue>2</issue><fpage>234</fpage><lpage>246</lpage><history><date date-type="received"><day>24</day><month>8</month><year>2018</year></date><date date-type="accepted"><day>21</day><month>12</month><year>2018</year></date></history><permissions><copyright-statement>Copyright 2019 Cancer Biology & Medicine</copyright-statement><copyright-year>2019</copyright-year><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by-nc-sa/4.0/"><license-p>This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License. To view a copy of this license, visit
<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc-sa/4.0/">http://creativecommons.org/licenses/by-nc-sa/4.0/</ext-link></license-p></license></permissions><abstract><sec><title>Objective</title><p>Patients with <italic>BRAF</italic>-mutant colorectal cancer (CRC) have a poor prognosis. Molecular status is not currently used to select which drug to use in combination with radiotherapy. Our aim was to identify drugs that radiosensitise CRC cells with known <italic>BRAF</italic> status.
</p></sec><sec><title>Methods</title><p>We screened 298 oncological drugs with and without ionising radiation in colorectal cancer cells isogenic for <italic>BRAF</italic>. Hits from rank product analysis were validated in a 16-cell line panel of human CRC cell lines, using clonogenic survival assays and xenograft models <italic>in vivo</italic>.
</p></sec><sec><title>Results</title><p>Most consistently identified hits were drugs targeting cell growth/proliferation or DNA damage repair. The most effective class of drugs that radiosensitised wild-type and mutant cell lines was PARP inhibitors. In clonogenic survival assays, talazoparib produced a radiation enhancement ratio of 1.9 in DLD1 (<italic>BRAF</italic>-wildtype) cells and 1.8 in RKO (<italic>BRAF</italic> V600E) cells. In DLD1 xenografts, talazoparib significantly increased the inhibitory effect of radiation on tumour growth (<italic>P</italic> ≤ 0.01).
</p></sec><sec><title>Conclusions</title><p>Our method for screening large drug libraries for radiosensitisation has identified PARP inhibitors as promising radiosensitisers of colorectal cancer cells with wild-type and mutant <italic>BRAF</italic> backgrounds.
</p></sec></abstract><kwd-group kwd-group-type="author-created"><kwd>Radiosensitizer</kwd><kwd>colorectal cancer</kwd><kwd>PARP inhibitor</kwd><kwd>radiotherapy</kwd></kwd-group></article-meta></front><body><sec id="s02"><label></label><title>Introduction</title><p>Colorectal cancer (CRC) is one of the most common forms of cancer, accounting for approximately 1 in 10 new cancer diagnoses worldwide in 2012<sup><xref rid="b1" ref-type="bibr">1</xref></sup>. Radiotherapy is commonly used to treat rectal cancers prior to surgery or to treat inoperable colorectal metastases, in the form of stereotactic body radiotherapy or selective internal radiotherapy<sup><xref rid="b2" ref-type="bibr">2</xref>-<xref rid="b4" ref-type="bibr">4</xref></sup>.
</p><p>International standard combination therapy for rectal cancer, radiotherapy delivered with 5-fluorouracil (5FU) as a radiosensitiser, is given either as an infusion or as an oral prodrug (capecitabine). There is currently no molecular basis for the selection of patients for radiotherapy, nor for the selection of any alternative drug to use as a radiosensitiser. With the current standard, sufficient downsizing by chemoradiotherapy is obtained by approximately half of patients treated<sup><xref rid="b5" ref-type="bibr">5</xref></sup>. There is scope for improving the radiotherapy approaches currently offered to patients. Clinical trials have added additional drugs to 5FU as a combination radiosensitising approach<sup><xref rid="b6" ref-type="bibr">6</xref>,<xref rid="b7" ref-type="bibr">7</xref></sup> without molecular selection, but these trials have not changed the international standard.
</p><p>Colorectal tumours have a heterogeneous molecular background<sup><xref rid="b8" ref-type="bibr">8</xref></sup>. Commonly occurring CRC mutations that may be prognostic or can affect treatment decisions include <italic>KRAS</italic>, <italic>BRAF</italic> and <italic>PIK3CA</italic> mutations, which are found in 42%, 9% and 13% of CRC patients respectively<sup><xref rid="b9" ref-type="bibr">9</xref></sup>. KRAS, BRAF and PIK3CA are vital components of two main cellular signalling pathways; RAS/MEK/ERK and PI3K/AKT/mTOR; strongly inter-connected pathways that play central roles in tumorigenesis by regulating cell survival, proliferation, metabolism, and motility. The <italic>KRAS</italic> gene is a member of the oncogenic <italic>RAS</italic> gene family and binds to effector kinases including BRAF and phosphatidylinositol 3-kinase (PI3K). The <italic>PIK3CA</italic> gene encodes the PI3K p110α subunit, which interacts with RAS proteins<sup><xref rid="b10" ref-type="bibr">10</xref></sup>.
</p><p>The commonest <italic>BRAF</italic> mutation in colorectal cancer, the V600E substitution, results in elevated kinase activity and constitutive downstream MEK and ERK phosphorylation<sup><xref rid="b11" ref-type="bibr">11</xref>,<xref rid="b12" ref-type="bibr">12</xref></sup>. The presence of <italic>BRAF</italic> V600E in advanced CRC correlates with poor prognosis with markedly worse progression after chemotherapy<sup><xref rid="b13" ref-type="bibr">13</xref>-<xref rid="b15" ref-type="bibr">15</xref></sup>. <italic>BRAF</italic> mutation is predictive of poor response to cetuximab in metastatic CRC, also observed for <italic>KRAS</italic> and <italic>PIK3CA</italic> mutations<sup><xref rid="b16" ref-type="bibr">16</xref>-<xref rid="b18" ref-type="bibr">18</xref></sup>. Although patients with <italic>BRAF</italic>-mutant cancers do less well with chemotherapy, anti-EGFR therapies and surgery<sup><xref rid="b19" ref-type="bibr">19</xref></sup>, there is currently no suggestion that they benefit less from radiotherapy. Although <italic>BRAF</italic> mutation is relatively rare in rectal cancer, radiotherapy can also be used to treat inoperable liver metastases from CRC. It has been suggested that CRC liver metastases respond less well to radiotherapy than liver metastases from other primary malignancies<sup><xref rid="b20" ref-type="bibr">20</xref></sup>, hence the addition of a radiosensitising drug may be of value to improve the therapeutic index during radiotherapy<sup><xref rid="b21" ref-type="bibr">21</xref></sup>.
</p><p>Our aim was to develop a radiosensitiser drug discovery assay enabling identification of drugs that will enhance radiotherapy more effectively than the current standard, 5FU, and demonstrate activity in defined molecular backgrounds. Firstly, we developed a high throughput screen (HTS), in CRC cell lines, to identify drugs that could be effective radiosensitisers in the context of <italic>BRAF</italic> V600E activating mutations. The drugs identified during the screen were validated across an extensive panel of human CRC cell lines, selected to represent aspects of the molecular landscape of CRC; including <italic>BRAF</italic> V600E in both MSI and MSS backgrounds, and a spectrum of <italic>KRAS</italic>, <italic>PIK3CA</italic> and <italic>p53</italic> mutations. Such cell line panels recapitulate the different subtypes found in CRC, are representative of genetic alterations found in primary cancers and are good predictors of clinical efficacy during drug development programmes<sup><xref rid="b22" ref-type="bibr">22</xref></sup>. Here, we use this model to test new drug-radiotherapy combinations for the first time, identifying PARP inhibitors as the most strongly radiosensitising class of agent before validating by clonogenic survival assays and <italic>in vivo</italic> xenograft studies.
</p></sec><sec id="s03"><label></label><title>Materials and methods</title><sec id="s03.01"><label></label><title>Cell lines, drug library and irradiations</title><p>The parental CRC cell lines RKO (<italic>BRAF V600E/V600E/WT</italic>) and VACO432 (<italic>V600E/WT</italic>) and their isogenic pairs RKO-T29 (<italic>BRAF WT/-/-</italic>) and VACO432-VT1 (BRAF WT/-) were a gift from Sandra Van Schaeybroeck, Queens University, Belfast, UK (mutation status confirmed by sequencing). The panel of colorectal cancer cell lines utilised for cell proliferation assays was obtained from Prof. Walter Bodmer, University of Oxford, UK. The cell line panel is listed in <bold><xref rid="TableS1" ref-type="table">Supplementary Table S1</xref></bold>, and has been previously described<sup><xref rid="b22" ref-type="bibr">22</xref></sup>. Non-malignant cell lines were obtained from Prof. Gillies McKenna, University of Oxford, UK. All cell lines were used within 12 passages, or where necessary, replenished using frozen aliquots of the initial passage. Isogenic cell lines were grown in McCoy's 5A (Modified) Medium, and other cell lines in DMEM; both supplemented with 10% Fetal Bovine Serum and 1 × penicillin/streptomycin (Thermofisher Scientific Inc., MA, USA), in a 37°C, 5% CO<sub>2</sub>, humidified incubator. The small compound anti-cancer drug library was provided in 384-well plate format (Target Discovery Institute, University of Oxford), and contained 222 drugs from the TDI Extended Oncology Drugs Library (ODL) and 76 from the NCI Developmental Therapeutics Program (DTP) Approved Oncology Drug set (<bold><xref rid="TableS2" ref-type="table">Supplementary Table S2</xref></bold>).
</p><p>A GSR D1 irradiator (Gamma-Service Medical GmbH, Leipzig, Germany) a Cs-137 source, (dose rate 1.5 Gy/min) was used for cell irradiations. For xenografts, a RS320 X-ray irradiator (Gulmay Limited, Byfleet, UK) was used (1.6 Gy/min), with lead shielding to localise dose to tumor. Dosimetry was calculated from optical density of scanned Gafchromic EBT3 film (Ashland, NJ, USA), corrected and calibrated to the National Physical Laboratory (Teddington, UK) primary standard.</p></sec><sec id="s03.02"><label></label><title>High-throughput drug screen with ionising radiation</title><p>Methodology and data analysis followed internationally recognised high-throughput screening guidelines<sup><xref rid="b23" ref-type="bibr">23</xref></sup>. <italic>BRAF V600E</italic> isogenic RKO and VACO432 cells were seeded in 52 μL/well by Flexdrop (PerkinElmer, MA, USA). Seeding density in 384-well plates was 300 cells/well (RKO) and 1,000 cells/well (VACO432). Eighteen hours after seeding, cells were screened with 298 oncological drugs, in 5-fold dilutions from 10 μM–16 nM. Janus workstations (PerkinElmer, MA, USA) were used to transfer 13 μL of compound from library plate to cell culture plates. Positive controls were PI103 and vorinostat, negative controls were vehicle (DMSO) alone. After 6 h, plates were either mock-irradiated, or irradiated with 4 Gy. Media was replaced 24 h following treatment, and surviving cells allowed to proliferate for five doubling times as optimised in preliminary screens. Cell viability was measured by resazurin (10 μg/mL) in phenol red-free DMEM. Metabolically viable cells reduce resazurin to fluorescent resorufin, which was quantified by PerkinElmer Envision microplate reader (540 nm excitation/590 nm emission). Control wells reached 90%–100% confluency at the time of assay performance, control irradiated wells were around 60% confluent. Raw data were normalized by rescaling to plate mean intensity and to negative controls. Quality plots were contrasted to assess artifacts and reproducibility. Normalized data Z are presented, as the applied rescaling by plate mean is effectively a z-score standardization. Selection of candidate hits was based on rank product analysis, adapting a published method<sup><xref rid="b24" ref-type="bibr">24</xref></sup>. Specifically, for each pair of conditions (i.e. with/without irradiation), the differences between normalised screen intensities were calculated for each well, hence each drug. These differences are presented as Delta-Z (ΔZ) scores. Rank product applied to these differences identified compounds producing large and consistent changes. Probability of false discovery was computed by permutation, with <italic>n</italic> = 100. Analyses were implemented in R version 2.1 (https://cran.r-project.org/); heatmaps were generated by modifying D3.js libraries (https://d3js.org/).
</p></sec><sec id="s03.03"><label></label><title>Cell proliferation and colony formation assays</title><p>Our method for comparison of IC<sub>50</sub> in the presence or absence of radiation has been described previously<sup><xref rid="b25" ref-type="bibr">25</xref></sup>. Clonogenic survival was measured following a standard method, with plating efficiency and surviving fractions calculated as described<sup><xref rid="b26" ref-type="bibr">26</xref></sup>. Briefly, cells were seeded into 10 cm culture dishes, normally 500 cells/plate (for 0 Gy plates), increasing by 10-fold for each 4 Gy administered, to 500,000 cells/plate (12 Gy). After attachment (overnight), cells were drug-treated, and six hours later exposed to 0, 4, 8 or 12 Gy radiation. Culture medium was replaced 24 hours post-irradiation, plates were incubated to form visible colonies > 50 cells (10 – 15 days) and fixed with 0.4% methylene blue in methanol. Survival curves were fitted using Graphpad Prism v7.0A. Radiation enhancement ratio (RER) was obtained from the ratio of radiation dose at 1% survival of vehicle compared with drug treated cells.
</p></sec><sec id="s03.04"><label></label><title>Xenograft studies</title><p>Animal experiments were performed following local ethical review under licence from the UK Home Office (ASPA 1986, revised January 2013). Female Balb/c nude mice (6–8 weeks old) were anaesthetised with 2% isoflurane and subcutaneously injected with 50% matrigel containing 5x10<sup>6</sup> DLD1 cells or 5 × 10<sup>6</sup> RKO/mouse (<italic>n</italic> = 24) into the back. When tumor volume reached 100 mm<sup>3</sup>, mice were randomly placed into 4 groups (<italic>n</italic> = 6/group). Oral treatments were by gavage, in two doses on the first and fourth days of treatment. Group (1) received vehicle only, 10% dimethylacetamide/6% solutol HS/PBS (0.1mL/10 g body weight). Group (2) received talazoparib; 0.1 mg/kg in vehicle. Radiation treatments comprised 2 × 5 Gy, localised to the tumor, also on the first and fourth days of treatment. Group (3) received radiation only, 5 Gy one hour after each vehicle treatment. Group (4) received combination treatment, 5 Gy one hour after each talazoparib treatment. Tumor size was measured by caliper 3 × per week. Mice were sacrificed when tumours reached 400 mm<sup>3</sup> or 42 days following the first treatment. Tumours were formalin fixed and stained for the hypoxia marker CA9 as previously described<sup><xref rid="b27" ref-type="bibr">27</xref></sup>.
</p></sec></sec><sec id="s04"><label></label><title>Results</title><sec id="s04.01"><label></label><title>Development of a high throughput screen with ionising radiation</title><p>In order to identify drugs that radiosensitise CRC cells mutated for BRAF V600E, isogenic cell lines containing either BRAF V600E or BRAF WT variants were screened against a 298-compound library of approved anticancer drugs. Mutation status for KRAS, PIK3CA and p53 for these cell lines is shown in <bold><xref ref-type="fig" rid="Figure1">Figure 1A</xref></bold>, with the screen protocol outlined in <bold><xref ref-type="fig" rid="Figure1">Figure 1B</xref></bold>.
</p><fig id="Figure1" orientation="portrait" position="float"><label>1</label><caption><p>High-throughput screening of FDA approved cancer drugs to identify which drugs should be used for radiosensitisation in the context of single gene mutations in colorectal cancer.</p></caption><alt-text>(A, B) CRC cells isogenic for BRAF V600E and with defined KRAS, PIK3CA and p53 status were screened with the DTP approved oncology drug library +/- irradiation and allowed to grow for five doubling times. Cell viability was compared between irradiated and non-irradiated plates. (C) Raw data were normalized by rescaling both to the plate mean and negative controls, and quality plots contrasted. (D) Heatmaps were generated for each individual plate. ΔZ scores were calculated between irradiated and non-irradiated plates. Selection of candidate hits was based on a rank product method (see methods). Probability of false discovery was computed by permutation, with 100 permutations. (E) Example heatmap generated for one of the HTS plates. Hits were identified as drugs with a ΔZ score significantly higher than expected by chance when irradiated and non-irradiated samples were compared.</alt-text><graphic xlink:href="cbm-16-2-234-1"></graphic></fig><p>A prerequisite for high-throughput detection of radiosensitisers is an assay that is predictive of the effects of drug/ radiation combinations on clonogenic cell survival. Extended incubation following irradiation improves correlation with radiosensitisation<sup><xref rid="b28" ref-type="bibr">28</xref></sup>, and we incorporated 5 days incubation following radiation treatment; improving correlation to clonogenic survival, but avoiding compromises to cell metabolism and thus assay performance<sup><xref rid="b29" ref-type="bibr">29</xref></sup>. Serial dilution of cells in the presence of resazurin showed equivalent fluorescence, linear in relation to cell number, for both non-irradiated cells, and cells 5 days post-irradiation (data not shown). This indicates that the metabolic assay was a good surrogate for cell number at this timepoint.
</p><p>Screens were carried out in duplicate and quality plots demonstrated good reproducibility (<bold><xref ref-type="fig" rid="Figure1">Figure 1C</xref></bold>), with mean Pearson correlation between pairs of replicates of 0.88 and average Z factor of 0.58 for irradiated and 0.53 for non-irradiated plates. Cell viability was compared between normalized irradiated and non-irradiated plates, generating heatmaps of the difference, ΔZ, for each compound. Hit selection (<bold><xref ref-type="fig" rid="Figure1">Figure 1D</xref></bold>) was based on rank product analysis, with the probability of false discovery computed by permutations (see Materials and methods). Potential hits were drugs that sensitised the BRAF-mutant isogenic variant, at one or more concentrations, with probability of false positive (PFP) ≤ 0.05. Some plates showed a pronounced ‘edge effect’, and for this reason, analysis was repeated considering the edge wells as a separate population (<bold><xref ref-type="fig" rid="Figure1">Figure 1E</xref></bold>). Hits with significant ΔZ score between irradiated and non-irradiated samples, with radiosensitisation factor < 1 (normalised against control plates) and <italic>P</italic>-value ≤ 0.05 were selected as significant. Positive controls were consistently identified as hits, with ΔZ scores ≤ 2, comparable to results obtained in manual assays.
</p></sec><sec id="s04.02"><label></label><p>BRAF V600E screen in isogenic cell lines following irradiation</p><p>Drugs were ranked according to radiosensitisation against <italic>BRAF</italic>-mutated cells. The fifteen drugs with the highest significance against <italic>BRAF</italic>-mutated cells are shown in <bold><xref rid="Table1" ref-type="table">Table 1</xref></bold>. Seven hits have previously been identified as radiosensitisers in the published literature<sup><xref rid="b30" ref-type="bibr">30</xref>-<xref rid="b36" ref-type="bibr">36</xref></sup>, helping to validate our methodology. Five hits were inhibitors of RAS/RAF/MEK/ERK pathway (trametinib, TAK-733, pimasertib, doramapoimod and dactolisib), predominantly acting in <italic>BRAF</italic> WT and V600E. Eight drugs reached significance in the <italic>BRAF</italic>-mutant cell line but not in <italic>BRAF</italic> WT, including the CHK1 inhibitor, PF477736. Another CHK1 inhibitor, AZD7762, radiosensitised both <italic>BRAF</italic> variants.
</p><table-wrap id="Table1" orientation="portrait" position="float"><label>1</label><caption><p>Fifteen radiosensitisers identified for <italic>BRAF</italic>-mutant cells
</p></caption><table frame="hsides" rules="groups"><thead><tr><td style="class:table_top_border" align="left" valign="middle" rowspan="1" colspan="1">Compound</td><td style="class:table_top_border" align="left" valign="middle" rowspan="1" colspan="1">Effective concentration
<break></break>in RKO (BRAF mut) (μM)
</td><td style="class:table_top_border" align="left" valign="middle" rowspan="1" colspan="1">Effective concentration
<break></break>in RKO (BRAF WT) (μM)
</td><td style="class:table_top_border" align="left" valign="middle" rowspan="1" colspan="1">Mechanism of action</td></tr></thead><tfoot><tr><td colspan="4" align="justify" rowspan="1">RKO colorectal cancer cells <italic>BRAF</italic> V600E or WT were screened with 298 approved oncology drugs alone or in combination with irradiation. Radiosensitisation factors were calculated from the ratio of fluorescence of irradiated versus non-irradiated plates. The most significant hits for <italic>BRAF</italic>-mutant variant RKO cells are shown; each hit has radiosensitisation factor < 1, PFP ≤0.05 and <italic>P</italic>-values ≤0.05; ‘ns’ indicates that significance was not reached in the <italic>BRAF</italic> WT cell line for the drug tested.
</td></tr></tfoot><tbody><tr><td style="class:table_top_border2" align="left" valign="middle" rowspan="1" colspan="1">Dactolisib</td><td style="class:table_top_border2" align="left" valign="middle" rowspan="1" colspan="1">0.016, 0.4</td><td style="class:table_top_border2" align="left" valign="middle" rowspan="1" colspan="1">0.016</td><td style="class:table_top_border2" align="left" valign="middle" rowspan="1" colspan="1">Dual PI3K/mTOR inhibitor</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Panobinastat</td><td align="left" valign="middle" rowspan="1" colspan="1">0.016</td><td align="left" valign="middle" rowspan="1" colspan="1">ns</td><td align="left" valign="middle" rowspan="1" colspan="1">HDAC inhibitor</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Trametinib</td><td align="left" valign="middle" rowspan="1" colspan="1">0.016</td><td align="left" valign="middle" rowspan="1" colspan="1">0.016</td><td align="left" valign="middle" rowspan="1" colspan="1">MEK inhibitor</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">ABT-199</td><td align="left" valign="middle" rowspan="1" colspan="1">0.08</td><td align="left" valign="middle" rowspan="1" colspan="1">0.08</td><td align="left" valign="middle" rowspan="1" colspan="1">Bcl-2 inhibitor</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Olaparib</td><td align="left" valign="middle" rowspan="1" colspan="1">0.08</td><td align="left" valign="middle" rowspan="1" colspan="1">ns</td><td align="left" valign="middle" rowspan="1" colspan="1">PARP inhibitor</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Tosedostat</td><td align="left" valign="middle" rowspan="1" colspan="1">0.08</td><td align="left" valign="middle" rowspan="1" colspan="1">ns</td><td align="left" valign="middle" rowspan="1" colspan="1">Peptidase inhibitor</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">AZD 7762</td><td align="left" valign="middle" rowspan="1" colspan="1">0.08</td><td align="left" valign="middle" rowspan="1" colspan="1">0.08</td><td align="left" valign="middle" rowspan="1" colspan="1">Chk inhibitor</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Pimasertib</td><td align="left" valign="middle" rowspan="1" colspan="1">0.4, 0.08</td><td align="left" valign="middle" rowspan="1" colspan="1">0.08</td><td align="left" valign="middle" rowspan="1" colspan="1">MEK inhibitor</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">PF477736</td><td align="left" valign="middle" rowspan="1" colspan="1">0.08</td><td align="left" valign="middle" rowspan="1" colspan="1">ns</td><td align="left" valign="middle" rowspan="1" colspan="1">Chk1 inhibitor</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">17-AAG</td><td align="left" valign="middle" rowspan="1" colspan="1">0.08</td><td align="left" valign="middle" rowspan="1" colspan="1">ns</td><td align="left" valign="middle" rowspan="1" colspan="1">Hsp90 inhibitor</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Doramapimod</td><td align="left" valign="middle" rowspan="1" colspan="1">0.08</td><td align="left" valign="middle" rowspan="1" colspan="1">ns</td><td align="left" valign="middle" rowspan="1" colspan="1">p38 MAPK inhibitor</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Danusertib</td><td align="left" valign="middle" rowspan="1" colspan="1">0.08</td><td align="left" valign="middle" rowspan="1" colspan="1">ns</td><td align="left" valign="middle" rowspan="1" colspan="1">aurora kinase inhibitor</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Serdametan</td><td align="left" valign="middle" rowspan="1" colspan="1">0.4</td><td align="left" valign="middle" rowspan="1" colspan="1">0.4</td><td align="left" valign="middle" rowspan="1" colspan="1">MDM2 inhibitor</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Tak-733</td><td align="left" valign="middle" rowspan="1" colspan="1">0.4</td><td align="left" valign="middle" rowspan="1" colspan="1">0.4</td><td align="left" valign="middle" rowspan="1" colspan="1">MEK inhibitor</td></tr><tr><td style="class:table_bottom_border" align="left" valign="middle" rowspan="1" colspan="1">Auranofin</td><td style="class:table_bottom_border" align="left" valign="middle" rowspan="1" colspan="1">0.4</td><td style="class:table_bottom_border" align="left" valign="middle" rowspan="1" colspan="1">ns</td><td style="class:table_bottom_border" align="left" valign="middle" rowspan="1" colspan="1">Gold complex</td></tr></tbody></table></table-wrap><p>The poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, significantly increased sensitivity to irradiation in <italic>BRAF</italic> V600E RKO cells. In a separate screen of <italic>BRAF</italic> isogenic Vaco432 cells, olaparib also radiosensitised <italic>BRAF</italic> V600E Vaco432 cells at 16 nM and 80 nM (<italic>P</italic> ≤ 0.05, data not shown). Based on these data, radiosensitisation by PARP inhibitors (PARPi) in RKO isogenic for V600E and WT, was validated by long-term proliferation assay at a broad concentration range and by clonogenic cell survival assay (<bold><xref ref-type="fig" rid="Figure2">Figure 2</xref></bold>). Olaparib as a single agent had little effect on survival, but combination treatment caused a significant increase in radiation sensitivity, albeit with similar effect in both <italic>BRAF</italic> WT and V600E variants.
</p><fig id="Figure2" orientation="portrait" position="float"><label>2</label><caption><p>Validation of radiosensitisation effects of olaparib in BRAF-mutant and BRAF-WT isogenic CRC cells.</p></caption><alt-text>Confirmation of radiosensitisation by olaparib in BRAF mutant and WT RKO cells by: (A) Long-term cell proliferation assays, showing separation (red arrows) between IC50 curves normalised for radiation effect, indicating significant radiosensitisation (BRAF-mutant: P ≤ 0.001; BRAF-WT: P ≤ 0.01, calculated by paired t -test). (B) Clonogenic survival assays, showing significant radiation enhancement by 0.1–1 μM olaparib at 1% cell survival (BRAF-mutant: P ≤ 0.05; BRAF-WT: P ≤ 0.001), calculated by one-way ANOVA in multiple comparison tests). Data show the mean of n = 3 experiments ± SEM (*P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001).</alt-text><graphic xlink:href="cbm-16-2-234-2"></graphic></fig></sec><sec id="s04.03"><label></label><title>Radiosensitisation in an extended CRC cell line panel</title><p>To validate the screen, we used a cell line panel inclusive of the different molecular subtypes of CRC. We specifically prioritised the drug hits with the most immediate scope for translation to clinical trials in combination with radiotherapy. The cell line panel was selected so that several cell lines exhibited each gene mutation of interest. Fifteen cell lines with defined <italic>BRAF</italic>, <italic>p53</italic>, <italic>KRAS</italic>, <italic>PIK3CA</italic> and mismatch repair status were used. The compounds chosen for further testing are shown in <bold><xref rid="Table2" ref-type="table">Table 2</xref></bold>, along with <italic>p</italic>-values indicating whether significant IC<sub>50</sub> shift was observed following normalisation for radiation effect. The complete IC<sub>50</sub> results determined by these assays are shown in <bold><xref rid="TableS3" ref-type="table">Supplementary Table S3</xref></bold>.
</p><table-wrap id="Table2" orientation="portrait" position="float"><label>2</label><caption><p><italic>P</italic>- values for radiosensitisation by 11 drugs across a panel of 15 CRC cell lines
</p></caption><table frame="hsides" rules="groups"><thead><tr><td style="class:table_top_border;padding-top:9pt;font-size:6.6pt" align="left" valign="top" colspan="2" rowspan="1">Cell line</td><td style="class:table_top_border;padding-top:9pt;font-size:6.6pt" align="left" valign="top" rowspan="1" colspan="1">LS411</td><td style="class:table_top_border;padding-top:9pt;font-size:6.6pt" align="left" valign="top" rowspan="1" colspan="1">Vaco5</td><td style="class:table_top_border;padding-top:9pt;font-size:6.6pt" align="left" valign="top" rowspan="1" colspan="1">RKO</td><td style="class:table_top_border;padding-top:9pt;font-size:6.6pt" align="left" valign="top" rowspan="1" colspan="1">HT29</td><td style="class:table_top_border;padding-top:9pt;font-size:6.6pt" align="left" valign="top" rowspan="1" colspan="1">OXCO4</td><td style="class:table_top_border;padding-top:9pt;font-size:6.6pt" align="left" valign="top" rowspan="1" colspan="1">CCK81</td><td style="class:table_top_border;padding-top:9pt;font-size:6.6pt" align="left" valign="top" rowspan="1" colspan="1">HCA7</td><td style="class:table_top_border;padding-top:9pt;font-size:6.6pt" align="left" valign="top" rowspan="1" colspan="1">DLD1</td><td style="class:table_top_border;padding-top:9pt;font-size:6.6pt" align="left" valign="top" rowspan="1" colspan="1">CW2</td><td style="class:table_top_border;padding-top:9pt;font-size:6.6pt" align="left" valign="top" rowspan="1" colspan="1">C10</td><td style="class:table_top_border;padding-top:9pt;font-size:6.6pt" align="left" valign="top" rowspan="1" colspan="1">HT55</td><td style="class:table_top_border;padding-top:9pt;font-size:6.6pt" align="left" valign="top" rowspan="1" colspan="1">C99</td><td style="class:table_top_border;padding-top:9pt;font-size:6.6pt" align="left" valign="top" rowspan="1" colspan="1">Colo678</td><td style="class:table_top_border;padding-top:9pt;font-size:6.6pt" align="left" valign="top" rowspan="1" colspan="1">SW403</td><td style="class:table_top_border;padding-top:9pt;font-size:6.6pt" align="left" valign="top" rowspan="1" colspan="1">SW1222</td></tr></thead><tfoot><tr><td colspan="17" align="justify" rowspan="1">A panel of fifteen colorectal cell lines, selected for <italic>BRAF</italic> status in a heterogeneous mutational background, were treated with 11 drugs with or without 4 Gy radiation. Radiosensitisation shown is for the clinical radiosensitiser, 5-fluorouracil; two positive control drugs, SAHA and PI103; and compounds selected on the basis of primary screen <italic>P</italic>-values and potential clinical utility. Significance was determined by paired <italic>t</italic>-test on IC<sub>50</sub> curve values following normalisation for radiation; ‘+’ indicates significant radiosensitisation, with the <italic>P</italic>-value indicated.
</td></tr></tfoot><tbody><tr><td align="left" valign="top" colspan="2" style="class:table_top_border2;padding-top:9pt;font-size:6.6pt" rowspan="1">BRAF</td><td align="left" valign="top" style="class:table_top_border2;padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">BRAF V600E</td><td align="left" valign="top" style="class:table_top_border2;padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">BRAF V600E</td><td align="left" valign="top" style="class:table_top_border2;padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">BRAF V600E</td><td align="left" valign="top" style="class:table_top_border2;padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">BRAF V600E</td><td align="left" valign="top" style="class:table_top_border2;padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">BRAFV600E</td><td align="left" valign="top" style="class:table_top_border2;padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">BRAFWT</td><td align="left" valign="top" style="class:table_top_border2;padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">BRAFWT</td><td align="left" valign="top" style="class:table_top_border2;padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">BRAFWT</td><td align="left" valign="top" style="class:table_top_border2;padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">BRAFWT</td><td align="left" valign="top" style="class:table_top_border2;padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">BRAFWT</td><td align="left" valign="top" style="class:table_top_border2;padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">BRAFWT</td><td align="left" valign="top" style="class:table_top_border2;padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">BRAFWT</td><td align="left" valign="top" style="class:table_top_border2;padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">BRAFWT</td><td align="left" valign="top" style="class:table_top_border2;padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">BRAFWT</td><td align="left" valign="top" style="class:table_top_border2;padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">BRAFWT</td></tr><tr><td align="left" valign="top" colspan="2" style="padding-top:9pt;font-size:6.6pt" rowspan="1">MSI status</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">MSI</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">MSI</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">MSI</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">MSS</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">MSS</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">MSI</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">MSI</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">MSI</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">MSI</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">MSS</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">MSS</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">MSS</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">MSS</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">MSS</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">MSS</td></tr><tr><td align="left" valign="top" colspan="2" style="padding-top:9pt;font-size:6.6pt" rowspan="1">KRAS</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">KRAS WT</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">KRAS WT</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">KRAS WT</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">KRAS WT</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">KRAS WT</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">KRAS WT</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">KRAS WT</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">KRAS G13D</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">KRAS P140H</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">KRAS WT</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">KRAS WT</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">KRAS WT</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">KRAS G12D</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">KRAS G12V</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">KRAS A146V</td></tr><tr><td align="left" valign="top" colspan="2" style="class:table_bottom_border2;padding-top:9pt;font-size:6.6pt" rowspan="1">EGFR</td><td align="left" valign="top" style="class:table_bottom_border2;padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">EGFR MUT</td><td align="left" valign="top" style="class:table_bottom_border2;padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">EGFR WT</td><td align="left" valign="top" style="class:table_bottom_border2;padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">EGFR WT</td><td align="left" valign="top" style="class:table_bottom_border2;padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">EGFR WT</td><td align="left" valign="top" style="class:table_bottom_border2;padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">Not known</td><td align="left" valign="top" style="class:table_bottom_border2;padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">EGFR Y1069C</td><td align="left" valign="top" style="class:table_bottom_border2;padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">EGFR WT</td><td align="left" valign="top" style="class:table_bottom_border2;padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">EGFR WT</td><td align="left" valign="top" style="class:table_bottom_border2;padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">EGFR G544*FS</td><td align="left" valign="top" style="class:table_bottom_border2;padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">EGFR WT</td><td align="left" valign="top" style="class:table_bottom_border2;padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">EGFR WT</td><td align="left" valign="top" style="class:table_bottom_border2;padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">EGFR WT</td><td align="left" valign="top" style="class:table_bottom_border2;padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">EGFR WT</td><td align="left" valign="top" style="class:table_bottom_border2;padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">EGFR WT</td><td align="left" valign="top" style="class:table_bottom_border2;padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">EGFR WT</td></tr><tr><td align="left" valign="top" style="class:table_bottom_border2;padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">Compound</td><td align="left" valign="top" style="class:table_bottom_border2;padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">Target</td><td colspan="15" align="left" valign="top" style="class:table_bottom_border2;padding-top:9pt;font-size:6.6pt" rowspan="1">Radiosensitisation response (+ indicates significant radiosensitisation, with <italic>P</italic> value given below)
</td></tr><tr><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">5-fluoro-
<break></break>uracil
</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">Thymidylate synthase</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+<italic>p</italic>≤0.01
</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td></tr><tr><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">SAHA</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">HDAC</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.05</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.05</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.05</td></tr><tr><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">PI-103</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">PI3K/
<break></break>DNAPK/
<break></break>mTOR
</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.05</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.05</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.05</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td></tr><tr><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">Olaparib</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">PARP</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td></tr><tr><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">Rucaparib</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">PARP</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.05</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.05</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.05</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td></tr><tr><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">AZD-7762</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">CHK1 and 2</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.05</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.05</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.05</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.05</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td></tr><tr><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">PF477736</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">CHK1 and 2</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.05</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.05</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.05</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.05</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.05</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.05</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.05</td></tr><tr><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">AZD-6244</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">MEK1 and 2</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.05</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.05</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.05</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td></tr><tr><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">Trametinib</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">MEK1 and 2</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.05</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.05</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.05</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.05</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td></tr><tr><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">Mitoxantrone</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">TOPO II</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.05</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.05</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.05</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.05</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">+≤ 0.01</td><td align="left" valign="top" style="padding-top:9pt;font-size:6.6pt" rowspan="1" colspan="1">ns</td></tr><tr><td style="class:table_bottom_border;padding-top:9pt;font-size:6.6pt" align="left" valign="top" rowspan="1" colspan="1">Vemurafenib</td><td style="class:table_bottom_border;padding-top:9pt;font-size:6.6pt" align="left" valign="top" rowspan="1" colspan="1">BRAF V600E</td><td style="class:table_bottom_border;padding-top:9pt;font-size:6.6pt" align="left" valign="top" rowspan="1" colspan="1">ns</td><td style="class:table_bottom_border;padding-top:9pt;font-size:6.6pt" align="left" valign="top" rowspan="1" colspan="1">ns</td><td style="class:table_bottom_border;padding-top:9pt;font-size:6.6pt" align="left" valign="top" rowspan="1" colspan="1">ns</td><td style="class:table_bottom_border;padding-top:9pt;font-size:6.6pt" align="left" valign="top" rowspan="1" colspan="1">ns</td><td style="class:table_bottom_border;padding-top:9pt;font-size:6.6pt" align="left" valign="top" rowspan="1" colspan="1">ns</td><td style="class:table_bottom_border;padding-top:9pt;font-size:6.6pt" align="left" valign="top" rowspan="1" colspan="1">ns</td><td style="class:table_bottom_border;padding-top:9pt;font-size:6.6pt" align="left" valign="top" rowspan="1" colspan="1">ns</td><td style="class:table_bottom_border;padding-top:9pt;font-size:6.6pt" align="left" valign="top" rowspan="1" colspan="1">ns</td><td style="class:table_bottom_border;padding-top:9pt;font-size:6.6pt" align="left" valign="top" rowspan="1" colspan="1">ns</td><td style="class:table_bottom_border;padding-top:9pt;font-size:6.6pt" align="left" valign="top" rowspan="1" colspan="1">ns</td><td style="class:table_bottom_border;padding-top:9pt;font-size:6.6pt" align="left" valign="top" rowspan="1" colspan="1">ns</td><td style="class:table_bottom_border;padding-top:9pt;font-size:6.6pt" align="left" valign="top" rowspan="1" colspan="1">ns</td><td style="class:table_bottom_border;padding-top:9pt;font-size:6.6pt" align="left" valign="top" rowspan="1" colspan="1">ns</td><td style="class:table_bottom_border;padding-top:9pt;font-size:6.6pt" align="left" valign="top" rowspan="1" colspan="1">ns</td><td style="class:table_bottom_border;padding-top:9pt;font-size:6.6pt" align="left" valign="top" rowspan="1" colspan="1">ns</td></tr></tbody></table></table-wrap><p>From these assays, olaparib and rucaparib displayed potent radiosensitising ability across multiple cell lines. IC<sub>50</sub> curves (normalised for radiation effect) were significantly different (<italic>P</italic> ≤ 0.01) for all except three cell lines; namely, C10, CW2 and Colo678 (<bold><xref rid="Table2" ref-type="table">Table 2</xref></bold>).
</p><p>Both Chk1 inhibitors, and trametinib, were also effective radiosensitisers in the majority of cell lines tested. Vemurafenib was ineffective in <italic>BRAF</italic> WT (IC<sub>50</sub> frequently not reached), but showed some efficacy in <italic>BRAF</italic> mutated cell lines, (not significant for radiosensitisation). This limited effect may arise from feedback activation of EGFR, PI3K or alternative signaling pathways, reducing vemurafenib efficacy in CRC when compared to melanoma<sup><xref rid="b37" ref-type="bibr">37</xref></sup>.
</p></sec><sec id="s04.04"><label></label><title>Validation of radiosensitisation by PARP inhibitors with clonogenic survival assays</title><p>As PARPi were the most effective radiosensitisers of the CRC cell line panel, clonogenic survival assays were used to measure radiation enhancement ratios (RERs) in 3 cell lines that were strongly radiosensitised (> 10-fold IC<sub>50</sub> shift) and 3 cell lines with IC<sub>50</sub> shift < 10-fold. To potentially improve PARPi radiosensitisation of these resistant cell lines, a more trapping PARPi, talazoparib, was included in these assays. Survival curves ( <bold><xref ref-type="fig" rid="Figure3">Figure 3</xref></bold>), and RERs (<bold><xref rid="Table3" ref-type="table">Table 3</xref></bold>) reflected the proliferation assay results: Olaparib and rucaparib significantly radiosensitised RKO, DLD1, and HT29 compared to vehicle-treated cells, while radiosensitisation of HT55, Colo678, and C10 was limited – although significant for HT55 cells treated with rucaparib. Talazoparib significantly radiosensitised all cell lines tested, and was overall the most effective radiosensitiser (average RERs 1.21–1.92), followed by rucaparib (average RERs 1.15–1.41) and finally olaparib (average RERs 1.12–1.4).
</p><fig id="Figure3" orientation="portrait" position="float"><label>3</label><caption><p>Clonogenic assays to confirm radiosensitisation of multiple cell lines by PARP inhibitors.</p></caption><alt-text>(A) Colorectal cancer cell lines were plated, rested overnight, drugged and 6 hours later, the cells were either mock irradiated, or irradiated at 4, 8, or 12 Gy. Separation between the control (DMSO) and treated curves indicates radiosensitivity induced by the compound. (B) Human lung fibroblast (HFLA and MRC5) and retinal epithelial (RPE) non-malignant cell lines were drugged in an identical manner and irradiated with 0, 4 or 8 Gy to determine non-cancer cell survival following similar treatment. Data show mean of n =3 experiments±SEM.</alt-text><graphic xlink:href="cbm-16-2-234-3"></graphic></fig><table-wrap id="Table3" orientation="portrait" position="float"><label>3</label><caption><p>Radiation enhancement ratios of PARP inhibitors for colorectal cancer and non-malignant cell lines</p></caption><table frame="hsides" rules="groups"><thead><tr><td colspan="5" style="class:table_top_border" align="center" valign="middle" rowspan="1">Gene mutation status</td><td align="left" valign="middle" style="class:table_top_border" rowspan="1" colspan="1"></td><td colspan="3" style="class:table_top_border" align="left" valign="middle" rowspan="1">Radiation enhancement ratio (<italic>P</italic>-value)
</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1"></td><td style="class:table_top_border2" align="left" valign="middle" rowspan="1" colspan="1">BRAF</td><td style="class:table_top_border2" align="left" valign="middle" rowspan="1" colspan="1">KRAS</td><td style="class:table_top_border2" align="left" valign="middle" rowspan="1" colspan="1">PIK3CA</td><td style="class:table_top_border2" align="left" valign="middle" rowspan="1" colspan="1">p53</td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td style="class:table_top_border2" align="left" valign="middle" rowspan="1" colspan="1">Olaparib</td><td style="class:table_top_border2" align="left" valign="middle" rowspan="1" colspan="1">Rucaparib</td><td style="class:table_top_border2" align="left" valign="middle" rowspan="1" colspan="1">Talazoparib</td></tr></thead><tfoot><tr><td colspan="9" align="justify" rowspan="1">Radiation enhancement ratios were calculated from clonogenic survival assays (normalised, by plating efficiency, for effect of drug alone) and comprise the ratio of radiation dose leading to 1% cell survival to the radiation dose producing 1% survival in the combined treatment. Significance (<italic>P</italic> ≤ 0.05), displayed by in bold, was calculated by one-way ANOVA, with multiple comparisons of each drug against the DMSO control.
</td></tr></tfoot><tbody><tr><td style="class:table_top_border2" colspan="4" align="left" valign="middle" rowspan="1">CRC cell lines</td><td style="class:table_top_border2" align="left" valign="middle" rowspan="1" colspan="1"></td><td style="class:table_top_border2" align="left" valign="middle" rowspan="1" colspan="1"></td><td style="class:table_top_border2" align="left" valign="middle" rowspan="1" colspan="1"></td><td style="class:table_top_border2" align="left" valign="middle" rowspan="1" colspan="1"></td><td style="class:table_top_border2" align="left" valign="middle" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">RKO</td><td align="left" valign="middle" rowspan="1" colspan="1">p.V600E</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">p.H1047R</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="1" colspan="1"><bold>1.48 (<italic>P</italic> ≤ 0.05)</bold></td><td align="left" valign="middle" rowspan="1" colspan="1"><bold>1.41 (<italic>P</italic> ≤ 0.05)</bold></td><td align="left" valign="middle" rowspan="1" colspan="1"><bold>1.71 (<italic>P</italic> ≤ 0.001)</bold></td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">HT29</td><td align="left" valign="middle" rowspan="1" colspan="1">p.V600E</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">R273H</td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="1" colspan="1"><bold>1.44 (<italic>P</italic> ≤ 0.01)</bold></td><td align="left" valign="middle" rowspan="1" colspan="1"><bold>1.28 (<italic>P</italic> ≤ 0.001)</bold></td><td align="left" valign="middle" rowspan="1" colspan="1"><bold>1.82 (<italic>P</italic> ≤ 0.001)</bold></td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">DLD1</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">G13D</td><td align="left" valign="middle" rowspan="1" colspan="1">p.E545K</td><td align="left" valign="middle" rowspan="1" colspan="1">S241F</td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="1" colspan="1"><bold>1.18 (<italic>P</italic> ≤ 0.01)</bold></td><td align="left" valign="middle" rowspan="1" colspan="1"><bold>1.21 (<italic>P</italic> ≤ 0.01)</bold></td><td align="left" valign="middle" rowspan="1" colspan="1"><bold>1.92 (<italic>P</italic> ≤ 0.001)</bold></td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">HT55</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">R213L</td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="1" colspan="1">1.21 (ns)</td><td align="left" valign="middle" rowspan="1" colspan="1"><bold>1.31 (<italic>P</italic> ≤ 0.01)</bold></td><td align="left" valign="middle" rowspan="1" colspan="1"><bold>1.39 (<italic>P</italic> ≤ 0.01)</bold></td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">C10</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">G245S</td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="1" colspan="1">1.12 (ns)</td><td align="left" valign="middle" rowspan="1" colspan="1">1.18 (ns)</td><td align="left" valign="middle" rowspan="1" colspan="1"><bold>1.48 (<italic>P</italic> ≤ 0.001)</bold></td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Colo678</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">G12D</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="1" colspan="1">1.12 (ns)</td><td align="left" valign="middle" rowspan="1" colspan="1">1.15 (ns)</td><td align="left" valign="middle" rowspan="1" colspan="1"><bold>1.21 (<italic>P</italic> ≤ 0.001)</bold></td></tr><tr><td colspan="9" align="left" valign="middle" rowspan="1">Non-malignant cell lines</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">HFLA</td><td align="left" valign="middle" rowspan="1" colspan="1">n/a</td><td align="left" valign="middle" rowspan="1" colspan="1">n/a</td><td align="left" valign="middle" rowspan="1" colspan="1">n/a</td><td align="left" valign="middle" rowspan="1" colspan="1">n/a</td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="1" colspan="1">1.09 (ns)</td><td align="left" valign="middle" rowspan="1" colspan="1"><bold>1.3 (<italic>P</italic> ≤ 0.05)</bold></td><td align="left" valign="middle" rowspan="1" colspan="1">1.29 (ns)</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">MRC5</td><td align="left" valign="middle" rowspan="1" colspan="1">n/a</td><td align="left" valign="middle" rowspan="1" colspan="1">n/a</td><td align="left" valign="middle" rowspan="1" colspan="1">n/a</td><td align="left" valign="middle" rowspan="1" colspan="1">n/a</td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="1" colspan="1"><bold>1.35 (<italic>P</italic> ≤ 0.05)</bold></td><td align="left" valign="middle" rowspan="1" colspan="1"><bold>1.34 (<italic>P</italic> ≤ 0.05)</bold></td><td align="left" valign="middle" rowspan="1" colspan="1"><bold>1.52 (<italic>P</italic> ≤ 0.01)</bold></td></tr><tr><td style="class:table_bottom_border" align="left" valign="middle" rowspan="1" colspan="1">RPE</td><td style="class:table_bottom_border" align="left" valign="middle" rowspan="1" colspan="1">n/a</td><td style="class:table_bottom_border" align="left" valign="middle" rowspan="1" colspan="1">n/a</td><td style="class:table_bottom_border" align="left" valign="middle" rowspan="1" colspan="1">n/a</td><td style="class:table_bottom_border" align="left" valign="middle" rowspan="1" colspan="1">n/a</td><td style="class:table_bottom_border" align="left" valign="middle" rowspan="1" colspan="1"></td><td style="class:table_bottom_border" align="left" valign="middle" rowspan="1" colspan="1">1.1 (ns)</td><td style="class:table_bottom_border" align="left" valign="middle" rowspan="1" colspan="1">1.07 (ns)</td><td style="class:table_bottom_border" align="left" valign="middle" rowspan="1" colspan="1"><bold>1.24 (<italic>P</italic> ≤ 0.01)</bold></td></tr></tbody></table></table-wrap><p>To indicate potential normal tissue toxicity, PARPi experiments were repeated in three non-malignant cell lines, HFLA, MRC5 and RPE. In clonogenic assays (<bold><xref rid="Table3" ref-type="table">Table 3</xref></bold>), these non-malignant cells were significantly radiosensitised by talazoparib. Radiosensitisation by rucaparib was significant for HFLA and MRC5, and radiosensitisation by olaparib was significant only for MRC5 cells (<italic>P</italic> ≤ 0.05).
</p></sec><sec id="s04.05"><label></label><title>Validation of PARP inhibitors as radiosensitisers in xenograft studies</title><p>The PARP inhibitor talazoparib was the most effective radiosensitiser and had not previously been tested with radiotherapy in animal CRC models. To confirm the <italic>in vitro</italic> radiosensitisation by PARPi in an <italic>in vivo</italic> model, talazoparib was tested against two cell lines that were effectively radiosensitised by the drug in 2D assays. Mice were inoculated with subcutaneous tumors consisting of RKO or DLD1 cells, and treated with talazoparib or vehicle, either alone or one hour before each of 2 × 5 Gy radiation treatments. In DLD1 cells (<bold><xref ref-type="fig" rid="Figure4">Figure 4A</xref></bold>), single treatment with talazoparib or radiation alone did not inhibit tumour growth. Combined talazoparib/radiation treatment was tolerated by the mice, and significantly reduced tumour growth compared with radiation alone (<italic>P</italic> ≤ 0.01). For the RKO cell xenograft model, there was no significant difference between the effect of radiation alone, and the radiation/talazoparib combination. Tumour histology, levels of perinecrotic hypoxia (CA9 staining) and necrosis were similar for both cell types (<bold><xref ref-type="fig" rid="Figure4">Figure 4B</xref></bold>).
</p><fig id="Figure4" orientation="portrait" position="float"><label>4</label><caption><p>Talazoparib significantly enhances the response of colorectal cancer cells grown <italic>in vivo</italic> to ionizing radiation.
</p></caption><alt-text>(A, B) Growth of tumour cells injected subcutaneously into the back of BALB/c nude mice, treated as indicated with either; vehicle; 0.1 mg/kg talazoparib; radiation (2 x 5 Gy); or 0.1 mg/kg talazoparib 1 hour prior to each of 2 x 5 Gy radiation doses. Treatment with talazoparib+radiation significantly slowed tumor growth for (A) DLD1 cells but not (B) RKO cells. (C, D) Representative images of tumours harvested from the vehicle treated group (at 400 mm3) show similar histology for both (C) DLD1 and (D) RKO xenografts including perinecrotic hypoxia (CA9 staining, brown) and tumor necrosis (N).</alt-text><graphic xlink:href="cbm-16-2-234-4"></graphic></fig></sec></sec><sec id="s05"><label></label><title>Discussion</title><p>The aim of this study was to identify treatment options to radiosensitise colorectal cancer cells in the context of key mutations that characterise the disease. Biopsies from CRC patients are routinely screened for <italic>BRAF</italic>, <italic>KRAS</italic> and <italic>PIK3CA</italic> mutations, but this information is not currently used in treatment decisions regarding radiotherapy. There is preclinical evidence that single gene alterations in cancer can determine the extent of radiosensitisation exerted by different drugs. Examples include mammalian AMP-activated protein kinase dependence of pancreatic cancer cells to radiosensitisation by metformin<sup><xref rid="b38" ref-type="bibr">38</xref></sup>, the role of mismatch repair deficiency in radiosensitisation of CRC cell lines by gemcitabine<sup><xref rid="b39" ref-type="bibr">39</xref>-<xref rid="b40" ref-type="bibr">40</xref></sup> and p53-dependent radiosensitisation by valproic acid<sup><xref rid="b41" ref-type="bibr">41</xref></sup>. Radiosensitisation drug discovery across different genetic backgrounds may enable a change from a “one size fits all” chemo- radiotherapy to the identification of the most appropriate drugs for radiotherapy based on the genetic profile of the cancer.
</p><p>To address our primary aim, we developed a novel high-throughput screen to test drug library/radiotherapy combination against cell lines. For drug repurposing, which allows more rapid translation in to the clinic, we used a library of drugs already in clinical use or in clinical trials. Previous investigators using more focused library screens have successfully identified radiosensitisers of CRC<sup><xref rid="b42" ref-type="bibr">42</xref></sup> and our study identified the same drugs with radiosensitising potential, the CHK inhibitor, AZD-7762, and the dual mTOR/PI3K inhibitor, dactosilib. We initially used isogenic cell lines to identify radiosensitisers active in a <italic>BRAF</italic> V600E background. Reassuringly, our results confirmed radiosensitisation by agents from drug classes previously shown to have radiosensitising activity in other published papers, such as inhibitors of the RAS/MEK/ERK, and PI3K/MTOR pathways. In addition, we identified compounds not previously known to be radiosensitisers (<bold><xref rid="Table1" ref-type="table">Table 1</xref></bold>). Of the drugs targeting mutated BRAF (vemurafenib, dabrafenib, RAF265), only vemurafenib reached the threshold for hit-detection in the screen, possibly because vemurafenib is a more potent radiosensitizer, at least compared with dabrafenib<sup><xref rid="b43" ref-type="bibr">43</xref></sup>.
</p><p>Cell lines manipulated by gene mutation might not be entirely representative of the molecular landscape of cancer in patients. We therefore validated results from isogenic cell lines in a panel of human colorectal cancer cell lines, inclusive of common CRC mutations and previously shown to be a useful model for drug development<sup><xref rid="b22" ref-type="bibr">22</xref>,<xref rid="b44" ref-type="bibr">44</xref></sup>. This approach was also novel since this cell line panel has not previously been used to test new drug-radiotherapy combinations. The results (shown in <bold><xref rid="Table2" ref-type="table">Table 2</xref></bold>), confirmed PARPi as significant radiosensitisers, notably across a much broader range of cell lines than 5FU, the current clinical standard, suggesting that 5FU may not be the optimal treatment for all CRC patients compared to newer and more targeted drugs. This reflects data in other studies in CRC, which show that radiosensitisation by 5FU varies depending on the cell line used<sup><xref rid="b45" ref-type="bibr">45</xref>,<xref rid="b46" ref-type="bibr">46</xref></sup>. Additionally, the timing of 5FU exposure may influence the degree of radiosensitisation<sup><xref rid="b47" ref-type="bibr">47</xref></sup>.
</p><p>In future, immunotherapy is likely to be of increasing importance in CRC treatment, although at present it is only used to treat the more immunogenic MSI-high tumours<sup><xref rid="b48" ref-type="bibr">48</xref></sup>. Despite this, radiotherapy is likely to remain an important treatment for rectal cancer and metastatic disease, particularly when the cost effectiveness of treatment is considered. The broad range of cell lines for which PARPi appear to be suitable radiosensitisers in this study may predict its potential future utility in a wide patient population.
</p><p>Three PARPi, olaparib, rucaparib, and niraparib, have been approved by the US FDA for the treatment of ovarian cancer, including BRCA-deficient tumours that have deficient homologous recombination repair. PARPi function by inhibiting the binding, or enzymatic activity, of PARP to single strand breaks in DNA. The absence of SSB repair leads to double strand break (DSB) formation at the approaching replication fork, and cell death. It has been shown that PARPi have an increased radiosensitising effect on DSB- repair deficient tumour cells compared with DSB- repair proficient lines<sup><xref rid="b49" ref-type="bibr">49</xref></sup>. Compared to olaparib and rucaparib, we found that talazoparib treatment led to higher RERs. PARPi affect cell proliferation by two main actions: inhibiting PARP enzymatic function, and by binding (‘trapping’) PARP to DNA<sup><xref rid="b50" ref-type="bibr">50</xref></sup>. Olaparib and rucaparib function primarily through inhibiting enzymatic function, whereas talazoparib ‘traps’ PARP at DNA damage sites, with increased anti-proliferative effect, potentially contributing to more effective radiosensitisation<sup><xref rid="b51" ref-type="bibr">51</xref>,<xref rid="b52" ref-type="bibr">52</xref></sup>.
</p><p>We proceeded to show that the PARP inhibitor, talazoparib, radiosensitised DLD1 xenografts <italic>in vivo</italic>. The combined treatment caused a prolonged tumour growth delay, in excess of the effects demonstrated elsewhere for combined 5FU/radiation treatment for HCT116<sup><xref rid="b45" ref-type="bibr">45</xref></sup> and WiDr<sup><xref rid="b53" ref-type="bibr">53</xref></sup> CRC xenografts. It is unclear why talazoparib did not significantly radiosensitise <italic>BRAF</italic> mutated RKO xenografts <italic>in vivo</italic>. It has been shown that <italic>BRAF</italic>-mutant early neoplastic lesions have upregulation of gene sets involved in aberrant DNA methylation<sup><xref rid="b54" ref-type="bibr">54</xref></sup> and that <italic>BRAF</italic>-mutant cancers can have distinct tumour-associated-stroma and components of the extracellular matrix that are different from wild-type cancers<sup><xref rid="b55" ref-type="bibr">55</xref></sup>. These complexities may explain the discrepancy between the highly significant results we obtained in 2D culture and the non-significant results we obtained <italic>in vivo</italic> using the same cell line. Future studies should consider the use of other models, such as patient-derived xenografts or immunocompetent mouse models, to explore this discrepancy further.
</p><p>Some investigators advocate preclinical comparison of non-malignant with malignant cell lines to identify cancer-specific drugs<sup><xref rid="b56" ref-type="bibr">56</xref>,<xref rid="b57" ref-type="bibr">57</xref></sup>. In our study, olaparib did not cause significant radiosensitisation of two non-malignant cell lines, HLA and RPE. An <italic>in vivo</italic> study of intestinal crypt damage, in which fractionated radiotherapy was combined with olaparib, did not appear to cause additional gut toxicity compared to radiotherapy without drug<sup><xref rid="b58" ref-type="bibr">58</xref></sup>. Contrastingly, clinical studies of PARPi have documented bowel toxicities as side effects of treatment<sup><xref rid="b59" ref-type="bibr">59</xref></sup> and total body irradiation of a p21-reporter mouse has shown that olaparib can exacerbate DNA damage in normal tissues when combined with radiation<sup><xref rid="b60" ref-type="bibr">60</xref></sup>. It should be noted that, in our study, rucaparib and talazoparib caused significant radiosensitisation of 2 non-malignant cells tested by clonogenic survival assays. Although talazoparib has already completed phase I development as a single agent<sup><xref rid="b61" ref-type="bibr">61</xref></sup>, we recommend that the normal tissue toxicity from the combination of PARPi with radiotherapy should be assessed further in preclinical normal tissue toxicity models and monitored closely in early-phase clinical trials.
</p><p>In conclusion, our novel approach to radiosensitisation drug discovery in cells isogenic for the <italic>BRAF V600E</italic> mutation, has led to the identification of PARPi as radiosensitisers for CRC. Validation in a broad panel of human CRC cell lines, and an <italic>in vivo</italic> xenograft model, has shown potentially broader radiosensitising activity than the current clinical standard of care, 5FU. Following toxicity evaluation of the combination of PARPi with radiotherapy in other preclinical models, we propose that PARP inhibition should be tested in combination with radiotherapy for rectal cancer or metastatic CRC treatment, with careful monitoring of potential toxicities.
</p></sec><sec id="s06"><title>Acknowledgements</title><p>This work was supported by Bowel Disease Research Foundation, Oxford Cancer Research Centre, the National Institute for Health Research University College London Hospitals Biomedical Research Centre, the Cancer Research UK University College London Experimental Cancer Medicine Centre, CRUK-UCL Centre Award (Grant No. C416/A25145), the Cancer Research UK Centers Network Accelerator Award Grant (Grant No. A21993) to the ART-NET Consortium, and the NIHR Oxford Biomedical Research Centre.</p></sec><sec id="s06-1"><label></label><title>Conflict of interest statement</title><p>No potential conflicts of interest are disclosed.</p></sec><sec sec-type="supplementary-material" id="sm01"><title>Supplementary material</title><table-wrap id="TableS1" orientation="portrait" position="float"><label>S1</label><caption><p>Details of the cell lines</p></caption><table frame="hsides" rules="groups"><thead><tr><td style="class:table_top_border" align="left" valign="middle" rowspan="1" colspan="1">Cell line</td><td style="class:table_top_border" align="left" valign="middle" rowspan="1" colspan="1"><italic>BRAF</italic></td><td style="class:table_top_border" align="left" valign="middle" rowspan="1" colspan="1"><italic>KRAS</italic></td><td style="class:table_top_border" align="left" valign="middle" rowspan="1" colspan="1"><italic>PIK3CA</italic></td><td style="class:table_top_border" align="left" valign="middle" rowspan="1" colspan="1"><italic>P53</italic></td><td style="class:table_top_border" align="left" valign="middle" rowspan="1" colspan="1">MSI/MSS</td><td style="class:table_top_border" align="left" valign="middle" rowspan="1" colspan="1">CIMP</td></tr></thead><tfoot><tr><td colspan="7" align="justify" rowspan="1">Table of cell lines comprising the panel for screen validation: Data is from Mouradov et al., Cancer Res. 2014; 74: 3238-47, except where indicated.
<break></break>† Indicates data from Prof. Walter Bodmer, personal communication. na. Indicates information not available
</td></tr></tfoot><tbody><tr><td style="class:table_top_border2" align="left" valign="middle" rowspan="1" colspan="1">C10</td><td style="class:table_top_border2" align="left" valign="middle" rowspan="1" colspan="1">WT</td><td style="class:table_top_border2" align="left" valign="middle" rowspan="1" colspan="1">WT</td><td style="class:table_top_border2" align="left" valign="middle" rowspan="1" colspan="1">WT</td><td style="class:table_top_border2" align="left" valign="middle" rowspan="1" colspan="1">WT</td><td style="class:table_top_border2" align="left" valign="middle" rowspan="1" colspan="1">MSS</td><td style="class:table_top_border2" align="left" valign="middle" rowspan="1" colspan="1">CIMP-</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">C99</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">MSS</td><td align="left" valign="middle" rowspan="1" colspan="1">CIMP-</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">CCK81</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">C420R, C472Y</td><td align="left" valign="middle" rowspan="1" colspan="1">P278H</td><td align="left" valign="middle" rowspan="1" colspan="1">MSI</td><td align="left" valign="middle" rowspan="1" colspan="1">CIMP-</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">COLO678</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">G12D</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">MSS</td><td align="left" valign="middle" rowspan="1" colspan="1">CIMP+</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">CW2 †</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">P140H</td><td align="left" valign="middle" rowspan="1" colspan="1">P283S</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">MSI</td><td align="left" valign="middle" rowspan="1" colspan="1">na.</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">DLD1</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">G13D</td><td align="left" valign="middle" rowspan="1" colspan="1">E545K</td><td align="left" valign="middle" rowspan="1" colspan="1">S241F</td><td align="left" valign="middle" rowspan="1" colspan="1">MSI</td><td align="left" valign="middle" rowspan="1" colspan="1">CIMP+</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">HCA7</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">P301fs*44</td><td align="left" valign="middle" rowspan="1" colspan="1">MSI</td><td align="left" valign="middle" rowspan="1" colspan="1">CIMP+</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">HT29</td><td align="left" valign="middle" rowspan="1" colspan="1">V600E</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">R273H</td><td align="left" valign="middle" rowspan="1" colspan="1">MSS</td><td align="left" valign="middle" rowspan="1" colspan="1">CIMP+</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">HT55</td><td align="left" valign="middle" rowspan="1" colspan="1">V600E</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">.R213L</td><td align="left" valign="middle" rowspan="1" colspan="1">MSS</td><td align="left" valign="middle" rowspan="1" colspan="1">CIMP-</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">LS411</td><td align="left" valign="middle" rowspan="1" colspan="1">V600E</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">Y126*</td><td align="left" valign="middle" rowspan="1" colspan="1">MSI</td><td align="left" valign="middle" rowspan="1" colspan="1">CIMP+</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">OXCO4 †</td><td align="left" valign="middle" rowspan="1" colspan="1">V600E</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">mutant</td><td align="left" valign="middle" rowspan="1" colspan="1">MSS</td><td align="left" valign="middle" rowspan="1" colspan="1">na.</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">RKO</td><td align="left" valign="middle" rowspan="1" colspan="1">V600E</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">H1047R</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">MSI</td><td align="left" valign="middle" rowspan="1" colspan="1">CIMP+</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">SW1222</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">A146V</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">MSS</td><td align="left" valign="middle" rowspan="1" colspan="1">CIMP-</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">SW403</td><td align="left" valign="middle" rowspan="1" colspan="1">WT</td><td align="left" valign="middle" rowspan="1" colspan="1">G12V</td><td align="left" valign="middle" rowspan="1" colspan="1">Q546K</td><td align="left" valign="middle" rowspan="1" colspan="1">E51*</td><td align="left" valign="middle" rowspan="1" colspan="1">MSS</td><td align="left" valign="middle" rowspan="1" colspan="1">CIMP-</td></tr><tr><td style="class:table_bottom_border" align="left" valign="middle" rowspan="1" colspan="1">VACO5 †</td><td style="class:table_bottom_border" align="left" valign="middle" rowspan="1" colspan="1">WT</td><td style="class:table_bottom_border" align="left" valign="middle" rowspan="1" colspan="1">WT</td><td style="class:table_bottom_border" align="left" valign="middle" rowspan="1" colspan="1">H1047R</td><td style="class:table_bottom_border" align="left" valign="middle" rowspan="1" colspan="1">mutant</td><td style="class:table_bottom_border" align="left" valign="middle" rowspan="1" colspan="1">MSI</td><td style="class:table_bottom_border" align="left" valign="middle" rowspan="1" colspan="1">na.</td></tr></tbody></table></table-wrap><table-wrap id="TableS2" orientation="portrait" position="float"><label>S2</label><caption><p>Anticancer drugs comprising the small compound library for the screen</p></caption><table frame="hsides" rules="groups"><thead><tr><td style="height:0.1;line-height:0.1;font-size:0.1pt" rowspan="1" colspan="1"></td><td style="height:0.1;line-height:0.1;font-size:0.1pt" rowspan="1" colspan="1"></td><td style="height:0.1;line-height:0.1;font-size:0.1pt" rowspan="1" colspan="1"></td><td style="height:0.1;line-height:0.1;font-size:0.1pt" rowspan="1" colspan="1"></td><td style="height:0.1;line-height:0.1;font-size:0.1pt" rowspan="1" colspan="1"></td></tr></thead><tfoot><tr><td colspan="5" align="justify" rowspan="1">Table of compounds tested from the combined TDI Extended Oncology Drugs Library (ODL) and the NCI Developmental Therapeutics Program (DTP) Approved Oncology Drug Library.</td></tr></tfoot><tbody><tr><td style="class:table_top_border" align="left" valign="top" rowspan="1" colspan="1">(5Z)-7-Oxozeaenol</td><td style="class:table_top_border" align="left" valign="top" rowspan="1" colspan="1">Bleomycin</td><td style="class:table_top_border" align="left" valign="top" rowspan="1" colspan="1">FK 506_Tacrolimus</td><td style="class:table_top_border" align="left" valign="top" rowspan="1" colspan="1">Mitomycin C</td><td style="class:table_top_border" align="left" valign="top" rowspan="1" colspan="1">Rapamycin (sirolimus)</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">(R)-Flurbiprofen (Tarenflurbil)</td><td align="left" valign="top" rowspan="1" colspan="1">BMS-754807</td><td align="left" valign="top" rowspan="1" colspan="1">FK-866 HCl_Daporinad</td><td align="left" valign="top" rowspan="1" colspan="1">Mitotane</td><td align="left" valign="top" rowspan="1" colspan="1">RD162</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">1-methyl-D-tryptophan, 95%</td><td align="left" valign="top" rowspan="1" colspan="1">BMS-911543</td><td align="left" valign="top" rowspan="1" colspan="1">Floxuridine</td><td align="left" valign="top" rowspan="1" colspan="1">Mitoxantrone</td><td align="left" valign="top" rowspan="1" colspan="1">RDEA119_Refametinib</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">17-AAG (Tanespimycin, Geldanamycin)</td><td align="left" valign="top" rowspan="1" colspan="1">Bortezomib</td><td align="left" valign="top" rowspan="1" colspan="1">Fludarabine</td><td align="left" valign="top" rowspan="1" colspan="1">MK-0752</td><td align="left" valign="top" rowspan="1" colspan="1">Ridaforolimus</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">17-DMAG (Alvespimycin)</td><td align="left" valign="top" rowspan="1" colspan="1">Bosutinib</td><td align="left" valign="top" rowspan="1" colspan="1">Fluorouracil</td><td align="left" valign="top" rowspan="1" colspan="1">MK-2206</td><td align="left" valign="top" rowspan="1" colspan="1">Rofecoxib (Vioxx)</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">2-methoxyestradiol (Panzem)</td><td align="left" valign="top" rowspan="1" colspan="1">Brivanib</td><td align="left" valign="top" rowspan="1" colspan="1">Flutamide</td><td align="left" valign="top" rowspan="1" colspan="1">MK-4827, HCl salt</td><td align="left" valign="top" rowspan="1" colspan="1">Romidepsin</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">4-hydroxytamoxifen</td><td align="left" valign="top" rowspan="1" colspan="1">Busulfan</td><td align="left" valign="top" rowspan="1" colspan="1">Fulvestrant</td><td align="left" valign="top" rowspan="1" colspan="1">MK1775</td><td align="left" valign="top" rowspan="1" colspan="1">Roscovitine_Selicilib</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Abitrexate/Methotrexate</td><td align="left" valign="top" rowspan="1" colspan="1">Cabazitaxel</td><td align="left" valign="top" rowspan="1" colspan="1">Galiellalactone</td><td align="left" valign="top" rowspan="1" colspan="1">MLN4924</td><td align="left" valign="top" rowspan="1" colspan="1">S-trityl-L-cysteine, 40 mM</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">ABT-199</td><td align="left" valign="top" rowspan="1" colspan="1">CAL-101</td><td align="left" valign="top" rowspan="1" colspan="1">GDC-0068</td><td align="left" valign="top" rowspan="1" colspan="1">MLN8237_Alisertib</td><td align="left" valign="top" rowspan="1" colspan="1">SB 743921</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">ABT-263 (Navitoclax)</td><td align="left" valign="top" rowspan="1" colspan="1">Camptothecin</td><td align="left" valign="top" rowspan="1" colspan="1">GDC-0941_Pictilisib</td><td align="left" valign="top" rowspan="1" colspan="1">Motesanib Di phosphate (AMG-706)</td><td align="left" valign="top" rowspan="1" colspan="1">Simvastatin</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">ABT-751</td><td align="left" valign="top" rowspan="1" colspan="1">Canertinib</td><td align="left" valign="top" rowspan="1" colspan="1">GDC-0980</td><td align="left" valign="top" rowspan="1" colspan="1">Nelarabine</td><td align="left" valign="top" rowspan="1" colspan="1">Sorafenib</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">ABT-869_Linifanib</td><td align="left" valign="top" rowspan="1" colspan="1">Capecitabine</td><td align="left" valign="top" rowspan="1" colspan="1">Gefitinib</td><td align="left" valign="top" rowspan="1" colspan="1">Nilotinib</td><td align="left" valign="top" rowspan="1" colspan="1">Sotrastaurin</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">ABT-888 (Veliparib)</td><td align="left" valign="top" rowspan="1" colspan="1">Carboplatin</td><td align="left" valign="top" rowspan="1" colspan="1">Gemcitabine HCl</td><td align="left" valign="top" rowspan="1" colspan="1">Nilutamide</td><td align="left" valign="top" rowspan="1" colspan="1">SR1 HCl</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">AC220_Quizartinib</td><td align="left" valign="top" rowspan="1" colspan="1">Carfilzomib</td><td align="left" valign="top" rowspan="1" colspan="1">Goserelin acetate</td><td align="left" valign="top" rowspan="1" colspan="1">Nitrogen mustard</td><td align="left" valign="top" rowspan="1" colspan="1">Stattic</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Acrichine</td><td align="left" valign="top" rowspan="1" colspan="1">Carmustine</td><td align="left" valign="top" rowspan="1" colspan="1">GSK 269962</td><td align="left" valign="top" rowspan="1" colspan="1">Nutlin-3</td><td align="left" valign="top" rowspan="1" colspan="1">Streptozocin</td></tr><tr><td align="left" valign="top" style="class:table_top_border" rowspan="1" colspan="1">AG-014699_Rucaparib</td><td align="left" valign="top" style="class:table_top_border" rowspan="1" colspan="1">Celecoxib</td><td align="left" valign="top" style="class:table_top_border" rowspan="1" colspan="1">GSK 650394</td><td align="left" valign="top" style="class:table_top_border" rowspan="1" colspan="1">NVP-AUY922</td><td align="left" valign="top" style="class:table_top_border" rowspan="1" colspan="1">Sunitinib</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Allopurinol</td><td align="left" valign="top" rowspan="1" colspan="1">CHIR-258 (Dovitinib)</td><td align="left" valign="top" rowspan="1" colspan="1">GSK1120212_ Trametinib</td><td align="left" valign="top" rowspan="1" colspan="1">NVP-BEZ235_Dactolisib</td><td align="left" valign="top" rowspan="1" colspan="1">TAK-733</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Altretamine</td><td align="left" valign="top" rowspan="1" colspan="1">Chlorambucil</td><td align="left" valign="top" rowspan="1" colspan="1">GSK2126458</td><td align="left" valign="top" rowspan="1" colspan="1">NVP-BGJ398</td><td align="left" valign="top" rowspan="1" colspan="1">TAK-901</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Amifostine</td><td align="left" valign="top" rowspan="1" colspan="1">Chloroquine diphosphate</td><td align="left" valign="top" rowspan="1" colspan="1">GSK2636771</td><td align="left" valign="top" rowspan="1" colspan="1">NVP-LDE225 (Diphosphate salt)</td><td align="left" valign="top" rowspan="1" colspan="1">Tamoxifen citrate</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Aminoglutethimide</td><td align="left" valign="top" rowspan="1" colspan="1">CHR 2797_Tosedostat</td><td align="left" valign="top" rowspan="1" colspan="1">HA-1077 (Fasudil)</td><td align="left" valign="top" rowspan="1" colspan="1">Obatoclax Mesylate (GX15-070)</td><td align="left" valign="top" rowspan="1" colspan="1">Tandutinib</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Aminolevulinic acid</td><td align="left" valign="top" rowspan="1" colspan="1">CI-994_Tacedinaline</td><td align="left" valign="top" rowspan="1" colspan="1">Homoharringtonine</td><td align="left" valign="top" rowspan="1" colspan="1">Olaparib</td><td align="left" valign="top" rowspan="1" colspan="1">Tasocitinib_Tofacitinib</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Amonafide</td><td align="left" valign="top" rowspan="1" colspan="1">Cisplatin aq</td><td align="left" valign="top" rowspan="1" colspan="1">Hydroxyurea</td><td align="left" valign="top" rowspan="1" colspan="1">OSI-027</td><td align="left" valign="top" rowspan="1" colspan="1">Temozolomide</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Anagrelide</td><td align="left" valign="top" rowspan="1" colspan="1">Cladribine</td><td align="left" valign="top" rowspan="1" colspan="1">I-BET151 (GSK1210151A)</td><td align="left" valign="top" rowspan="1" colspan="1">OSI-906_Linsitinib</td><td align="left" valign="top" rowspan="1" colspan="1">Teniposide</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Anastrozole</td><td align="left" valign="top" rowspan="1" colspan="1">Clafen (Cyclophos-phamide, Endoxan)</td><td align="left" valign="top" rowspan="1" colspan="1">Idarubicin HCl</td><td align="left" valign="top" rowspan="1" colspan="1">Oxaliplatin</td><td align="left" valign="top" rowspan="1" colspan="1">Tetramisole HCl</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">AP24534 (Ponatinib)</td><td align="left" valign="top" rowspan="1" colspan="1">Clofarabine</td><td align="left" valign="top" rowspan="1" colspan="1">Ifosfamide</td><td align="left" valign="top" rowspan="1" colspan="1">PAC-1</td><td align="left" valign="top" rowspan="1" colspan="1">TGX-221</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">ARQ 197_Tivantinib</td><td align="left" valign="top" rowspan="1" colspan="1">Clomifene citrate</td><td align="left" valign="top" rowspan="1" colspan="1">Imatinib</td><td align="left" valign="top" rowspan="1" colspan="1">Paclitaxel</td><td align="left" valign="top" rowspan="1" colspan="1">Thalidomide</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">ARRY-162_MEK-162</td><td align="left" valign="top" rowspan="1" colspan="1">CPI-613</td><td align="left" valign="top" rowspan="1" colspan="1">Imiquimod</td><td align="left" valign="top" rowspan="1" colspan="1">Panobinostat</td><td align="left" valign="top" rowspan="1" colspan="1">Thio-TEPA</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Arsenic(II<bold>I</bold>) oxide
</td><td align="left" valign="top" rowspan="1" colspan="1">Crenolanib</td><td align="left" valign="top" rowspan="1" colspan="1">INCB018424 (free base, Ruxolitinib)</td><td align="left" valign="top" rowspan="1" colspan="1">Pazopanib</td><td align="left" valign="top" rowspan="1" colspan="1">Thioguanine</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">AS703026_Pimasertib</td><td align="left" valign="top" rowspan="1" colspan="1">Crizotinib</td><td align="left" valign="top" rowspan="1" colspan="1">Indibulin</td><td align="left" valign="top" rowspan="1" colspan="1">PCI-32765_Ibrutinib</td><td align="left" valign="top" rowspan="1" colspan="1">Thiotepa</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Aspirin (Acetylsalicylic Acid)</td><td align="left" valign="top" rowspan="1" colspan="1">CUDC-101</td><td align="left" valign="top" rowspan="1" colspan="1">Iniparib (BSI-201, IND-71677)</td><td align="left" valign="top" rowspan="1" colspan="1">PD-0332991</td><td align="left" valign="top" rowspan="1" colspan="1">Tipifarnib (Zarnestra)</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">AT 101</td><td align="left" valign="top" rowspan="1" colspan="1">Cyclophosphamide</td><td align="left" valign="top" rowspan="1" colspan="1">INK128</td><td align="left" valign="top" rowspan="1" colspan="1">Pemetrexed</td><td align="left" valign="top" rowspan="1" colspan="1">Topotecan HCl</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">AT-406</td><td align="left" valign="top" rowspan="1" colspan="1">CYT-387_Momelotinib</td><td align="left" valign="top" rowspan="1" colspan="1">Irinotecan</td><td align="left" valign="top" rowspan="1" colspan="1">Pentostatin</td><td align="left" valign="top" rowspan="1" colspan="1">Toremifene citrate</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">AT9283</td><td align="left" valign="top" rowspan="1" colspan="1">Cytarabine HCl</td><td align="left" valign="top" rowspan="1" colspan="1">Ixabepilone</td><td align="left" valign="top" rowspan="1" colspan="1">Perifosine aq/PBS</td><td align="left" valign="top" rowspan="1" colspan="1">Tretinoin</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Atorvastatin Ca</td><td align="left" valign="top" rowspan="1" colspan="1">Dabrafenib Mesylate</td><td align="left" valign="top" rowspan="1" colspan="1">JNJ 26854165 (Serdemetan)</td><td align="left" valign="top" rowspan="1" colspan="1">PF 431396</td><td align="left" valign="top" rowspan="1" colspan="1">Triethylenemelamine</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Auranofin</td><td align="left" valign="top" rowspan="1" colspan="1">Dacarbazine</td><td align="left" valign="top" rowspan="1" colspan="1">JNJ_26481585_Quisinostat</td><td align="left" valign="top" rowspan="1" colspan="1">PF 477736</td><td align="left" valign="top" rowspan="1" colspan="1">Tubacin</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">AV-951 (Tivozanib)</td><td align="left" valign="top" rowspan="1" colspan="1">Dacomitinib (monohydrate) (PF-00299804)</td><td align="left" valign="top" rowspan="1" colspan="1">KX2-391</td><td align="left" valign="top" rowspan="1" colspan="1">PF-04691502</td><td align="left" valign="top" rowspan="1" colspan="1">Tubastatin A HCl</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">AVN944</td><td align="left" valign="top" rowspan="1" colspan="1">Dactinomycin</td><td align="left" valign="top" rowspan="1" colspan="1">Lapatinib, di-p-toluenesulfonate salt</td><td align="left" valign="top" rowspan="1" colspan="1">PF-04708671</td><td align="left" valign="top" rowspan="1" colspan="1">UCN-01</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Axitinib</td><td align="left" valign="top" rowspan="1" colspan="1">Dasatinib</td><td align="left" valign="top" rowspan="1" colspan="1">Lasofoxifene</td><td align="left" valign="top" rowspan="1" colspan="1">PF-2341066 (Crizotinib)</td><td align="left" valign="top" rowspan="1" colspan="1">Uracil mustard</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">AZ 3146</td><td align="left" valign="top" rowspan="1" colspan="1">Daunorubicin HCl</td><td align="left" valign="top" rowspan="1" colspan="1">Lenalidomide</td><td align="left" valign="top" rowspan="1" colspan="1">PF-3845</td><td align="left" valign="top" rowspan="1" colspan="1">Valproic acid</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Azacitidine</td><td align="left" valign="top" rowspan="1" colspan="1">DCC-2036_Rebastinib</td><td align="left" valign="top" rowspan="1" colspan="1">Lestaurtinib</td><td align="left" valign="top" rowspan="1" colspan="1">PF4800567 hydrochloride</td><td align="left" valign="top" rowspan="1" colspan="1">Valrubicin</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">AZD 7762 hydrochloride</td><td align="left" valign="top" rowspan="1" colspan="1">Decitabine</td><td align="left" valign="top" rowspan="1" colspan="1">Letrozole</td><td align="left" valign="top" rowspan="1" colspan="1">PF670462</td><td align="left" valign="top" rowspan="1" colspan="1">Vandetanib</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">AZD1152-HQPA</td><td align="left" valign="top" rowspan="1" colspan="1">Decitabine (Dacogen)</td><td align="left" valign="top" rowspan="1" colspan="1">Lomeguatrib</td><td align="left" valign="top" rowspan="1" colspan="1">PHA-739358 (Danusertib)</td><td align="left" valign="top" rowspan="1" colspan="1">Varespladib</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">AZD1480</td><td align="left" valign="top" rowspan="1" colspan="1">Deferoxamine mesylate</td><td align="left" valign="top" rowspan="1" colspan="1">Lomustine, CCNU</td><td align="left" valign="top" rowspan="1" colspan="1">PIK-75 HCl</td><td align="left" valign="top" rowspan="1" colspan="1">Vatalanib</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">AZD2014</td><td align="left" valign="top" rowspan="1" colspan="1">Dexamethasone (Decadron)</td><td align="left" valign="top" rowspan="1" colspan="1">LY 333531 mesylate- Ruboxistaurin</td><td align="left" valign="top" rowspan="1" colspan="1">Pilocarpine</td><td align="left" valign="top" rowspan="1" colspan="1">Vemurafenib</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">AZD4547</td><td align="left" valign="top" rowspan="1" colspan="1">Dexrazoxone</td><td align="left" valign="top" rowspan="1" colspan="1">LY2157299</td><td align="left" valign="top" rowspan="1" colspan="1">Pipobroman</td><td align="left" valign="top" rowspan="1" colspan="1">VER 155008</td></tr><tr><td align="left" valign="top" style="class:table_top_border" rowspan="1" colspan="1">AZD6244 (Selumetinib)</td><td align="left" valign="top" style="class:table_top_border" rowspan="1" colspan="1">Dinaciclib (SCH727965)</td><td align="left" valign="top" style="class:table_top_border" rowspan="1" colspan="1">LY2228820 (CP868569)</td><td align="left" valign="top" style="class:table_top_border" rowspan="1" colspan="1">PKC412_Midostaurin</td><td align="left" valign="top" style="class:table_top_border" rowspan="1" colspan="1">Vinblastine sulfate</td></tr><tr><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">AZD8055</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Docetaxel</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">LY2603618_Rabusertib</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Plerixafor</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Vincristine Sulfate (Oncovin)</td></tr><tr><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">BAY 73-4506_Regorafenib</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Doxorubicin</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">LY2784544_Gandotinib</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Plicamycin</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Vinorelbine tartrate</td></tr><tr><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Belinostat (PXD101)</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Doxorubicin HCl</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Masitinib</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">PLX4032_Vemurafenib</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Vismodegib</td></tr><tr><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Bendamustine HCl</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">EMD1214063</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">MDV3100_Enzaluamide</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Pralatrexate</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Vorinostat</td></tr><tr><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Bexarotene</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Entinostat</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Megestrol acetate</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Pravastatin</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">VX-11e</td></tr><tr><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">BI 2536</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Enzastaurin</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Melphalan</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Prednisolone</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">XAV-939</td></tr><tr><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">BI 6727_Volasertib</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Epothilone B (Patupilone)</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Mercaptopurine</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Prednisone</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">XL-147</td></tr><tr><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">BIBF 1120_Nintedanib</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Erlotinib HCl</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Metformin
<break></break>hydrochloride aq
</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Prima-1 Met</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">XL184_Cabozantinib</td></tr><tr><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">BIBW2992 (Tovok)_Afatinib</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Estramustine sodium phosphate</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Methotrexate</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Procarbazine</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">XL880 (Foretinib)</td></tr><tr><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Bicalutamide</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Etoposide</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Methoxsalen</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">PX-866_Sonolisib</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">YM155</td></tr><tr><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">BIIB021</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Everolimus</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Methylprednisolone</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Quinacrine HCl</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Zolendronic acid</td></tr><tr><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Bimatoprost</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">Exemestane</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">MGCD-265</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">R406_Tamatinib</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">ZSTK474</td></tr><tr><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">BIRB 796 (Doramapimod)</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">FG-4592</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">MGCD0103_Mocetinostat</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1">RAF265</td><td align="left" valign="top" style="padding-bottom:2pt" rowspan="1" colspan="1"></td></tr><tr><td style="class:table_bottom_border;padding-bottom:2pt" align="left" valign="top" rowspan="1" colspan="1">BKM-120_Buparlisib</td><td style="class:table_bottom_border;padding-bottom:2pt" align="left" valign="top" rowspan="1" colspan="1">Finasteride</td><td style="class:table_bottom_border" align="left" valign="top" rowspan="1" colspan="1">Mithramycin A</td><td style="class:table_bottom_border;padding-bottom:2pt;padding-bottom:2pt" align="left" valign="top" rowspan="1" colspan="1">Raloxifene HCl</td><td style="class:table_bottom_border;padding-bottom:2pt" align="left" valign="top" rowspan="1" colspan="1"></td></tr></tbody></table></table-wrap><table-wrap id="TableS3" orientation="portrait" position="float"><label>S3</label><caption><p>IC<sub>50</sub> (μM) for each drug at 0 and 4 Gy in a panel of colorectal cancer cell lines
</p></caption><table frame="hsides" rules="groups"><thead><tr><td style="class:table_top_border table_bottom_border2" align="left" valign="middle" rowspan="1" colspan="1">Cell line</td><td style="class:table_top_border table_bottom_border2" align="left" valign="middle" rowspan="1" colspan="1">5-FU IC<sub>50</sub></td><td style="class:table_top_border table_bottom_border2" align="left" valign="middle" rowspan="1" colspan="1">Vorinostat IC<sub>50</sub></td><td style="class:table_top_border table_bottom_border2" align="left" valign="middle" rowspan="1" colspan="1">PI-103 IC<sub>50</sub></td><td style="class:table_top_border table_bottom_border2" align="left" valign="middle" rowspan="1" colspan="1">Olaparib IC<sub>50</sub></td><td style="class:table_top_border table_bottom_border2" align="left" valign="middle" rowspan="1" colspan="1">Rucaparib IC<sub>50</sub></td><td style="class:table_top_border table_bottom_border2" align="left" valign="middle" rowspan="1" colspan="1">Mitoxantrone IC<sub>50</sub></td></tr></thead><tfoot><tr><td colspan="7" align="justify" rowspan="1">IC<sub>50</sub> was calculated using Graphpad Prism following normalisation for radiation effect, and is shown in μM, with 95% confidence limits in parenthesis.
<break></break>* Where the curve shape did not allow calculation of IC<sub>50</sub> in Graphpad, IC<sub>50</sub> was calculated manually by interpolation.
<break></break>* > indicates the highest concentration tested in cell lines where the IC <sub>50</sub> was not reached.
</td></tr></tfoot><tbody><tr><td align="left" valign="top" rowspan="1" colspan="1">LS411 0 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">24.67
<break></break> (17.58 to 35.46)
</td><td align="left" valign="top" rowspan="1" colspan="1">6.79
<break></break> (3.99 to 11.91)
</td><td align="left" valign="top" rowspan="1" colspan="1">5.23
<break></break> (3.47 to 8.12)
</td><td align="left" valign="top" rowspan="1" colspan="1">24.46
<break></break> (15.71 to 38.89)
</td><td align="left" valign="top" rowspan="1" colspan="1">*62.18</td><td align="left" valign="top" rowspan="1" colspan="1">16.75
<break></break> (12.32 to 22.98)
</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">LS411 4 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">21.95
<break></break> (12.37 to 40.8)
</td><td align="left" valign="top" rowspan="1" colspan="1">14.55
<break></break> (9.69 to 22.27)
</td><td align="left" valign="top" rowspan="1" colspan="1">2.76
<break></break> (1.57 to 4.96)
</td><td align="left" valign="top" rowspan="1" colspan="1">2.11
<break></break> (1.09 to 4.18)
</td><td align="left" valign="top" rowspan="1" colspan="1">1.72
<break></break> (0.49 to 8.54)
</td><td align="left" valign="top" rowspan="1" colspan="1">7.8
<break></break> (5.63 to 10.89)
</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">VACO5 0 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">2.54
<break></break> (1.95 to 3.35)
</td><td align="left" valign="top" rowspan="1" colspan="1">3.45
<break></break> (2.47 to 4.9)
</td><td align="left" valign="top" rowspan="1" colspan="1">1.91
<break></break> (1.05 to 3.58)
</td><td align="left" valign="top" rowspan="1" colspan="1">10.5
<break></break> (3.83 to 29.59)
</td><td align="left" valign="top" rowspan="1" colspan="1">34.03
<break></break> (21.2 to 58.03)
</td><td align="left" valign="top" rowspan="1" colspan="1">3.49
<break></break> (0.87 to 14.64)
</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">VACO5 4 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">0.99
<break></break> (0.83 to 1.19)
</td><td align="left" valign="top" rowspan="1" colspan="1">3.37
<break></break> (2.85 to 4)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.48
<break></break> (0.34 to 0.71)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.75
<break></break> (0.43 to 1.3)
</td><td align="left" valign="top" rowspan="1" colspan="1">3.07
<break></break> (0.61 to 11.91)
</td><td align="left" valign="top" rowspan="1" colspan="1">1.24
<break></break> (0.56 to 2.99)
</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">RKO 0 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">2.51
<break></break> (1.93 to 3.29)
</td><td align="left" valign="top" rowspan="1" colspan="1">6.51
<break></break> (3.89 to 11.26)
</td><td align="left" valign="top" rowspan="1" colspan="1">1.55
<break></break> (0.95 to 2.54)
</td><td align="left" valign="top" rowspan="1" colspan="1">8.63
<break></break> (4.32 to 17.22)
</td><td align="left" valign="top" rowspan="1" colspan="1">61.23
<break></break> (30.07 to 167.4)
</td><td align="left" valign="top" rowspan="1" colspan="1">9.75
<break></break> (6.21 to 15.44)
</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">RKO 4 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">1.15
<break></break> (0.73 to 1.90)
</td><td align="left" valign="top" rowspan="1" colspan="1">2.14
<break></break> (1.2 to 4.15)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.33
<break></break> (0.20 to 0.57)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.35
<break></break> (0.15 to 0.78)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.3
<break></break> (0.03 to 1.59)
</td><td align="left" valign="top" rowspan="1" colspan="1">2.9
<break></break> (1.59 to 5.46)
</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">HT29 0 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">9.12
<break></break> (6.67 to 12.66)
</td><td align="left" valign="top" rowspan="1" colspan="1">3.47
<break></break> (2.42 to 5.03)
</td><td align="left" valign="top" rowspan="1" colspan="1">* >20</td><td align="left" valign="top" rowspan="1" colspan="1">17.93
<break></break> (4.14 to 75.29)
</td><td align="left" valign="top" rowspan="1" colspan="1">51.82
<break></break> (33.61 to 86.34)
</td><td align="left" valign="top" rowspan="1" colspan="1">6.58
<break></break> (1.24 to 78.99)
</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">HT29 4 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">6.6
<break></break> (5.24 to 8.36)
</td><td align="left" valign="top" rowspan="1" colspan="1">4.18
<break></break> (2.6 to 6.94)
</td><td align="left" valign="top" rowspan="1" colspan="1">* 12.94</td><td align="left" valign="top" rowspan="1" colspan="1">2.21
<break></break> (1.25 to 3.55)
</td><td align="left" valign="top" rowspan="1" colspan="1">5.48
<break></break> (2.49 to 11.75)
</td><td align="left" valign="top" rowspan="1" colspan="1">3.06
<break></break> (0.88 to 12)
</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">OXCO4 0 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">16.71
<break></break> (14.13 to 19.85)
</td><td align="left" valign="top" rowspan="1" colspan="1">6.09
<break></break> (3.69 to 10.41)
</td><td align="left" valign="top" rowspan="1" colspan="1">2.42
<break></break> (1.82 to 3.24)
</td><td align="left" valign="top" rowspan="1" colspan="1">26.88
<break></break> (16.82 to 43.79)
</td><td align="left" valign="top" rowspan="1" colspan="1">13.11
<break></break> (10.42 to 16.58)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.89
<break></break> (0.61 to 1.33)
</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">OXCO4 4 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">9.45
<break></break> (7.92 to 11.32)
</td><td align="left" valign="top" rowspan="1" colspan="1">3.82
<break></break> (2.69 to 5.49)
</td><td align="left" valign="top" rowspan="1" colspan="1">1.13
<break></break> (0.87 to 1.47)
</td><td align="left" valign="top" rowspan="1" colspan="1">6.07
<break></break> (4.73 to 7.82)
</td><td align="left" valign="top" rowspan="1" colspan="1">2.5
<break></break> (1.74 to 3.61)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.59
<break></break> (0.44 to 0.78)
</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">CW2 0 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">20.19
<break></break> (15.17 to 27.24)
</td><td align="left" valign="top" rowspan="1" colspan="1">4.49
<break></break> (2.9 to 7.08)
</td><td align="left" valign="top" rowspan="1" colspan="1">4.97
<break></break> (3.14 to 8.17)
</td><td align="left" valign="top" rowspan="1" colspan="1">17.05
<break></break> (6.48 to 44.79)
</td><td align="left" valign="top" rowspan="1" colspan="1">36.91
<break></break> (30.48 to 45.16)
</td><td align="left" valign="top" rowspan="1" colspan="1">19.81
<break></break> (11.2 to 35.76)
</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">CW2 4 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">*20.1</td><td align="left" valign="top" rowspan="1" colspan="1">5.33
<break></break> (3.59 to 7.99)
</td><td align="left" valign="top" rowspan="1" colspan="1">4.21
<break></break> (1.49 to 14.87)
</td><td align="left" valign="top" rowspan="1" colspan="1">* >20</td><td align="left" valign="top" rowspan="1" colspan="1">* >30</td><td align="left" valign="top" rowspan="1" colspan="1">21.02
<break></break> (12.56 to 186)
</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">DLD1 0 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">8.6
<break></break> (6.77 to 10.99)
</td><td align="left" valign="top" rowspan="1" colspan="1">6.26
<break></break> (3.07 to 13.72)
</td><td align="left" valign="top" rowspan="1" colspan="1">1.69
<break></break> (0.94 to 3.08)
</td><td align="left" valign="top" rowspan="1" colspan="1">* >100</td><td align="left" valign="top" rowspan="1" colspan="1">*30.41</td><td align="left" valign="top" rowspan="1" colspan="1">4.08
<break></break> (1.49 to 12.46)
</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">DLD1 4 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">7.78
<break></break> (5.26 to 11.81)
</td><td align="left" valign="top" rowspan="1" colspan="1">3.25
<break></break> (2.02 to 5.42)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.52
<break></break> (0.29 to 0.95)
</td><td align="left" valign="top" rowspan="1" colspan="1">1.74
<break></break> (0.89 to 3.5)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.44
<break></break> (0.15 to 2.1)
</td><td align="left" valign="top" rowspan="1" colspan="1">1.9
<break></break> (1.33 to 2.72)
</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">CCK81 0 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">29.85
<break></break> (23.48 to 38)
</td><td align="left" valign="top" rowspan="1" colspan="1">10.4
<break></break> (5.37 to 21.34)
</td><td align="left" valign="top" rowspan="1" colspan="1">1.27
<break></break> (0.92 to 1.76)
</td><td align="left" valign="top" rowspan="1" colspan="1">>100</td><td align="left" valign="top" rowspan="1" colspan="1">*48.51</td><td align="left" valign="top" rowspan="1" colspan="1">*16.51</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">CCK81 4Gy</td><td align="left" valign="top" rowspan="1" colspan="1">20.77
<break></break> (16.64 to 26.01)
</td><td align="left" valign="top" rowspan="1" colspan="1">7.84
<break></break> (4.13 to 15.86)
</td><td align="left" valign="top" rowspan="1" colspan="1">1.07
<break></break> (0.81 to 1.44)
</td><td align="left" valign="top" rowspan="1" colspan="1">13.05
<break></break> (7.62 to 22.53)
</td><td align="left" valign="top" rowspan="1" colspan="1">45.05
<break></break> (11.83 to 105.1)
</td><td align="left" valign="top" rowspan="1" colspan="1">22.6
<break></break> (11.62 to 60.7)
</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">C10 0 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">43.38
<break></break> (31.27 to 60.93)
</td><td align="left" valign="top" rowspan="1" colspan="1">2.05
<break></break> (0.82 to 6.16)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.98
<break></break> (0.45 to 2.19)
</td><td align="left" valign="top" rowspan="1" colspan="1">* >100</td><td align="left" valign="top" rowspan="1" colspan="1">23.7
<break></break> (20.64 to 222.2)
</td><td align="left" valign="top" rowspan="1" colspan="1">3.92
<break></break> (1.84 to 8.96)
</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">C10 4 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">39.86
<break></break> (17.15 to 101.3)
</td><td align="left" valign="top" rowspan="1" colspan="1">10.21
<break></break> (1.3 to 74.5)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.53
<break></break> (0.27 to 1.17)
</td><td align="left" valign="top" rowspan="1" colspan="1">* >100</td><td align="left" valign="top" rowspan="1" colspan="1">22.4
<break></break> (6.87 to 130)
</td><td align="left" valign="top" rowspan="1" colspan="1">2.18
<break></break> (1.14 to 4.29)
</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">SW403 0 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">1.31
<break></break> (0.86 to 2.02)
</td><td align="left" valign="top" rowspan="1" colspan="1">17.71
<break></break> (7.57 to 49.28)
</td><td align="left" valign="top" rowspan="1" colspan="1">* >20</td><td align="left" valign="top" rowspan="1" colspan="1">6.18
<break></break> (1.46 to 26.89)
</td><td align="left" valign="top" rowspan="1" colspan="1">40.51
<break></break> (27.91 to 61.56)
</td><td align="left" valign="top" rowspan="1" colspan="1">2.17
<break></break> (0.94 to 5.27)
</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">SW403 4 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">0.73
<break></break> (0.49 to 1.09)
</td><td align="left" valign="top" rowspan="1" colspan="1">7.28
<break></break> (4.53 to 12.05)
</td><td align="left" valign="top" rowspan="1" colspan="1">10.81
<break></break> (5.35 to 27.22)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.85
<break></break> (0.28 to 2.46)
</td><td align="left" valign="top" rowspan="1" colspan="1">12.39
<break></break> (5.71 to 26.75)
</td><td align="left" valign="top" rowspan="1" colspan="1">1.46
<break></break> (0.66 to 3.41)
</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">COLO678 0 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">85
<break></break> (37.7 to 197.4)
</td><td align="left" valign="top" rowspan="1" colspan="1">8.68
<break></break> (1.84 to 64.49)
</td><td align="left" valign="top" rowspan="1" colspan="1">2.3
<break></break> (1.08 to 5.15)
</td><td align="left" valign="top" rowspan="1" colspan="1">* >200</td><td align="left" valign="top" rowspan="1" colspan="1">* 48.67</td><td align="left" valign="top" rowspan="1" colspan="1">5.96
<break></break> (2.98 to 12.18)
</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">COLO678 4 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">81.5
<break></break> (70.58 to 129.3)
</td><td align="left" valign="top" rowspan="1" colspan="1">*5.5</td><td align="left" valign="top" rowspan="1" colspan="1">2.24
<break></break> (1.09 to 4.85)
</td><td align="left" valign="top" rowspan="1" colspan="1">* >200</td><td align="left" valign="top" rowspan="1" colspan="1">* 45.79</td><td align="left" valign="top" rowspan="1" colspan="1">20.31
<break></break> (12.29 to 34.44)
</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">SW1222 0 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">10.58
<break></break> (5.80 to 20.42)
</td><td align="left" valign="top" rowspan="1" colspan="1">41.93
<break></break> (16.03 to 134)
</td><td align="left" valign="top" rowspan="1" colspan="1">* >20</td><td align="left" valign="top" rowspan="1" colspan="1">16.72
<break></break> (9.97 to 28.91)
</td><td align="left" valign="top" rowspan="1" colspan="1">9.78
<break></break> (4.56 to 22.31)
</td><td align="left" valign="top" rowspan="1" colspan="1">2.76
<break></break> (1.63 to 4.8)
</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">SW1222 4 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">3.23
<break></break> (2.19 to 4.75)
</td><td align="left" valign="top" rowspan="1" colspan="1">4.07
<break></break> (2.98 to 5.63)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.75
<break></break> (0.63 to 0.90)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.42
<break></break> (0.32 to 0.56)
</td><td align="left" valign="top" rowspan="1" colspan="1">* 0.32</td><td align="left" valign="top" rowspan="1" colspan="1">0.73
<break></break> (0.32 to 1.83)
</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">HCA7 0 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">27.64
<break></break> (22.63 to 33.87)
</td><td align="left" valign="top" rowspan="1" colspan="1">1.29
<break></break> (0.93 to 1.80)
</td><td align="left" valign="top" rowspan="1" colspan="1">2.95
<break></break> (1.71 to 5.26)
</td><td align="left" valign="top" rowspan="1" colspan="1">3.99
<break></break> (3.16 to 5.05)
</td><td align="left" valign="top" rowspan="1" colspan="1">48.51
<break></break> (35.36 to 68.98)
</td><td align="left" valign="top" rowspan="1" colspan="1">1.93
<break></break> (0.57 to 6.89)
</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">HCA7 4 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">19.82
<break></break> (16.49 to 23.89)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.82
<break></break> (0.70 to 0.97)
</td><td align="left" valign="top" rowspan="1" colspan="1">1.14
<break></break> (0.79 to 1.66)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.24
<break></break> (0.18 to 0.32)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.36
<break></break> (0.19 to 0.66)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.75
<break></break> (0.24 to 2.53)
</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">HT55 0 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">10.53
<break></break> (7.91 to 14.17)
</td><td align="left" valign="top" rowspan="1" colspan="1">2.11
<break></break> (1.51 to 3)
</td><td align="left" valign="top" rowspan="1" colspan="1">2.87
<break></break> (0.95 to 9.99)
</td><td align="left" valign="top" rowspan="1" colspan="1">41.07(4.96 to 28.01)</td><td align="left" valign="top" rowspan="1" colspan="1">12.2
<break></break> (8.31 to 18.19)
</td><td align="left" valign="top" rowspan="1" colspan="1">1.26
<break></break> (0.86 to 1.85)
</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">HT55 4 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">12.03
<break></break> (8.91 to 16.48)
</td><td align="left" valign="top" rowspan="1" colspan="1">3.14(1.99 to 5.10)</td><td align="left" valign="top" rowspan="1" colspan="1">2.58
<break></break> (1.85 to 3.63)
</td><td align="left" valign="top" rowspan="1" colspan="1">7.88
<break></break> (0.88 to 3.66)
</td><td align="left" valign="top" rowspan="1" colspan="1">1.47
<break></break> (0.4 to 5.18)
</td><td align="left" valign="top" rowspan="1" colspan="1">1.27
<break></break> (0.79 to 2.08)
</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">C99 0 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">3.34
<break></break> (2.11 to 5.72)
</td><td align="left" valign="top" rowspan="1" colspan="1">3.53
<break></break> (1.8 to 7.46)
</td><td align="left" valign="top" rowspan="1" colspan="1">23.77
<break></break> (8.94 to 31.98)
</td><td align="left" valign="top" rowspan="1" colspan="1">14.01
<break></break> (4.11 to 53.54)
</td><td align="left" valign="top" rowspan="1" colspan="1">39.28
<break></break> (21.29 to 81.87)
</td><td align="left" valign="top" rowspan="1" colspan="1">1.15
<break></break> (0.58 to 2.31)
</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">C99 4 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">4.44
<break></break> (2.37 to 8.86)
</td><td align="left" valign="top" rowspan="1" colspan="1">3
<break></break> (1.66 to 5.92)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.97
<break></break> (0.30 to 3.48)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.44
<break></break> (0.22 to 0.87)
</td><td align="left" valign="top" rowspan="1" colspan="1">14.2
<break></break> (0.16 to 18)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.49
<break></break> (0.27 to 0.92)
</td></tr><tr><td style="class:table_top_border2" align="left" valign="top" rowspan="1" colspan="1">Cell line</td><td style="class:table_top_border2" align="left" valign="top" rowspan="1" colspan="1">AZD-7762 IC<sub>50</sub></td><td style="class:table_top_border2" align="left" valign="top" rowspan="1" colspan="1">PF4777 IC<sub>50</sub></td><td style="class:table_top_border2" align="left" valign="top" rowspan="1" colspan="1">AZD-6244 IC<sub>50</sub></td><td style="class:table_top_border2" align="left" valign="top" rowspan="1" colspan="1">Trametinib IC<sub>50</sub></td><td style="class:table_top_border2" align="left" valign="top" rowspan="1" colspan="1">Vemurafenib IC<sub>50</sub></td><td style="class:table_top_border2" align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td style="class:table_top_border2" align="left" valign="top" rowspan="1" colspan="1">LS411 0 Gy</td><td style="class:table_top_border2" align="left" valign="top" rowspan="1" colspan="1">2.69
<break></break> (1.5 to 6.50)
</td><td style="class:table_top_border2" align="left" valign="top" rowspan="1" colspan="1">3.84
<break></break> (2.91 to 5.08)
</td><td style="class:table_top_border2" align="left" valign="top" rowspan="1" colspan="1">11.92
<break></break> (5.13 to 39.4)
</td><td style="class:table_top_border2" align="left" valign="top" rowspan="1" colspan="1">2.03
<break></break> (0.08 to 25.26)
</td><td style="class:table_top_border2" align="left" valign="top" rowspan="1" colspan="1">58.81
<break></break> (30.19 to 144.8)
</td><td style="class:table_top_border2" align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">LS411 4 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">0.41
<break></break> (0.25 to 0.69)
</td><td align="left" valign="top" rowspan="1" colspan="1">1.49
<break></break> (1.06 to 1.83)
</td><td align="left" valign="top" rowspan="1" colspan="1">6.94
<break></break> (2.62 to 24.83)
</td><td align="left" valign="top" rowspan="1" colspan="1">1.81
<break></break> (0.006 to 48.6)
</td><td align="left" valign="top" rowspan="1" colspan="1">20.39
<break></break> (4.63 to 210.7)
</td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">RKO 0 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">0.02
<break></break> (0.015 to 0.03)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.47
<break></break> (0.31 to 0.71)
</td><td align="left" valign="top" rowspan="1" colspan="1">*148.75</td><td align="left" valign="top" rowspan="1" colspan="1">0.09
<break></break> (0.03 to 0.3)
</td><td align="left" valign="top" rowspan="1" colspan="1">15.14
<break></break> (4.37 to 57.2)
</td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">RKO 4 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">0.005
<break></break> (0.004 to 0.008)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.19
<break></break> (0.15 to 0.25)
</td><td align="left" valign="top" rowspan="1" colspan="1">4.62
<break></break> (0.74 to 46.47)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.03
<break></break> (0.01 to 0.07)
</td><td align="left" valign="top" rowspan="1" colspan="1">4.57
<break></break> (0.99 to 29.93)
</td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">VACO5 0 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">0.05
<break></break> (0.03 to 0.11)
</td><td align="left" valign="top" rowspan="1" colspan="1">1.5
<break></break> (1.06 to 2.16)
</td><td align="left" valign="top" rowspan="1" colspan="1">14.81
<break></break> (7.95 to 29.18)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.01
<break></break> (0.007 to 0.017)
</td><td align="left" valign="top" rowspan="1" colspan="1">9.37
<break></break> (6.57 to 13.45)
</td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">VACO5 4 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">0.01
<break></break> (0.004 to 0.02)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.28
<break></break> (0.23 to 0.34)
</td><td align="left" valign="top" rowspan="1" colspan="1">7.08
<break></break> (4.28 to 11.86)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.003
<break></break> (0.003 to 0.004)
</td><td align="left" valign="top" rowspan="1" colspan="1">3.86
<break></break> (2.6 to 5.84)
</td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">HT29 0 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">0.03
<break></break> (0.02 to 0.06)
</td><td align="left" valign="top" rowspan="1" colspan="1">4.08
<break></break> (2.58 to 6.89)
</td><td align="left" valign="top" rowspan="1" colspan="1">2.34(1.02 to 5.62)</td><td align="left" valign="top" rowspan="1" colspan="1">0.02
<break></break> (0.01 to 0.04)
</td><td align="left" valign="top" rowspan="1" colspan="1">13.1
<break></break> (5.49 to 32.24)
</td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">HT29 4 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">0.01
<break></break> (0.003 to 0.03)
</td><td align="left" valign="top" rowspan="1" colspan="1">1.57
<break></break> (1.03 to 2.45)
</td><td align="left" valign="top" rowspan="1" colspan="1">1.87(0.62 to 6.39)</td><td align="left" valign="top" rowspan="1" colspan="1">0.01
<break></break> (0.007 to 0.02)
</td><td align="left" valign="top" rowspan="1" colspan="1">11.76
<break></break> (6.68 to 20.96)
</td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">OXCO4 0 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">2.14
<break></break> (1.39 to 3.73)
</td><td align="left" valign="top" rowspan="1" colspan="1">1.54
<break></break> (1.08 to 2.22)
</td><td align="left" valign="top" rowspan="1" colspan="1">3.04
<break></break> (1.76 to 5.35)
</td><td align="left" valign="top" rowspan="1" colspan="1">*0.15</td><td align="left" valign="top" rowspan="1" colspan="1">14.57
<break></break> (10.14 to 21.19)
</td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">OXCO4 4 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">0.17
<break></break> (0.13 to 0.22)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.76
<break></break> (0.54 to 1.09)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.82
<break></break> (0.33 to 2.4)
</td><td align="left" valign="top" rowspan="1" colspan="1">*0.06</td><td align="left" valign="top" rowspan="1" colspan="1">10.6
<break></break> (4.09 to 28.44)
</td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">CW2 0 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">2.16
<break></break> (1.17 to 5.32)
</td><td align="left" valign="top" rowspan="1" colspan="1">26.75
<break></break> (21.9 to 32.78)
</td><td align="left" valign="top" rowspan="1" colspan="1">1.72
<break></break> (0.47 to 9.39)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.46
<break></break> (0.2 to 1.24)
</td><td align="left" valign="top" rowspan="1" colspan="1">*53.05</td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">CW2 4 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">* >2</td><td align="left" valign="top" rowspan="1" colspan="1">20.75
<break></break> (6.06 to 71.96)
</td><td align="left" valign="top" rowspan="1" colspan="1">* >10</td><td align="left" valign="top" rowspan="1" colspan="1">0.18
<break></break> (0.076 to 0.44)
</td><td align="left" valign="top" rowspan="1" colspan="1">*49.07</td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">DLD1 0 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">0.14
<break></break> (0.1 to 0.21)
</td><td align="left" valign="top" rowspan="1" colspan="1">* 15.02</td><td align="left" valign="top" rowspan="1" colspan="1">* >20</td><td align="left" valign="top" rowspan="1" colspan="1">* >1</td><td align="left" valign="top" rowspan="1" colspan="1">*66.41</td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">DLD1 4 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">0.02
<break></break> (0.01 to 0.05)
</td><td align="left" valign="top" rowspan="1" colspan="1">5.46
<break></break> (2.36 to 12.91)
</td><td align="left" valign="top" rowspan="1" colspan="1">* >20</td><td align="left" valign="top" rowspan="1" colspan="1">0.08
<break></break> (0.02 to 0.59)
</td><td align="left" valign="top" rowspan="1" colspan="1">33.24
<break></break> (14.01 to 84.84)
</td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">CCK81 0 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">0.75
<break></break> (0.43 to 1.42)
</td><td align="left" valign="top" rowspan="1" colspan="1">* >10</td><td align="left" valign="top" rowspan="1" colspan="1">* >20</td><td align="left" valign="top" rowspan="1" colspan="1">*>1</td><td align="left" valign="top" rowspan="1" colspan="1">* >160</td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">CCK81 4Gy</td><td align="left" valign="top" rowspan="1" colspan="1">0.11
<break></break> (0.08 to 0.17)
</td><td align="left" valign="top" rowspan="1" colspan="1">* >10</td><td align="left" valign="top" rowspan="1" colspan="1">* >20</td><td align="left" valign="top" rowspan="1" colspan="1">* >1</td><td align="left" valign="top" rowspan="1" colspan="1">* >160</td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">C10 0 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">0.12
<break></break> (0.1 to 0.15)
</td><td align="left" valign="top" rowspan="1" colspan="1">*10.08</td><td align="left" valign="top" rowspan="1" colspan="1">*25.69</td><td align="left" valign="top" rowspan="1" colspan="1">0.68
<break></break> (0.26 to 3.31)
</td><td align="left" valign="top" rowspan="1" colspan="1">53.16
<break></break> (30.73 to 99.45)
</td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">C10 4 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">0.12
<break></break> (0.08 to 0.2)
</td><td align="left" valign="top" rowspan="1" colspan="1">* >10</td><td align="left" valign="top" rowspan="1" colspan="1">* >20</td><td align="left" valign="top" rowspan="1" colspan="1">0.29
<break></break> (0.13 to 0.74)
</td><td align="left" valign="top" rowspan="1" colspan="1">48.79
<break></break> (23.05 to 119.8)
</td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">SW403 0 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">0.26
<break></break> (0.18 to 0.37)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.79
<break></break> (0.44 to 1.41)
</td><td align="left" valign="top" rowspan="1" colspan="1">6.45
<break></break> (3.02 to 15.7)
</td><td align="left" valign="top" rowspan="1" colspan="1">*2.03</td><td align="left" valign="top" rowspan="1" colspan="1">* >80</td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">SW403 4 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">0.13
<break></break> (0.1 to 0.16)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.37
<break></break> (0.22 to 0.62)
</td><td align="left" valign="top" rowspan="1" colspan="1">1.71
<break></break> (1.08 to 2.76)
</td><td align="left" valign="top" rowspan="1" colspan="1">* 1.68</td><td align="left" valign="top" rowspan="1" colspan="1">* >80</td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">COLO678 0 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">* >2</td><td align="left" valign="top" rowspan="1" colspan="1">*25.14</td><td align="left" valign="top" rowspan="1" colspan="1">1.12
<break></break> (0.72 to 1.78)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.006
<break></break> (0.005 to 0.008)
</td><td align="left" valign="top" rowspan="1" colspan="1">* >80</td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">COLO678 4 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">* >2</td><td align="left" valign="top" rowspan="1" colspan="1">*25.39</td><td align="left" valign="top" rowspan="1" colspan="1">1.47
<break></break> (1.07 to 2.04)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.005
<break></break> (0.002 to 0.01)
</td><td align="left" valign="top" rowspan="1" colspan="1">* >80</td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">SW1222 0 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">0.07
<break></break> (0.05 to 0.1)
</td><td align="left" valign="top" rowspan="1" colspan="1">6.26
<break></break> (4.02 to 10.64)
</td><td align="left" valign="top" rowspan="1" colspan="1">3.75
<break></break> (0.64 to 45.5)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.23
<break></break> (0.09 to 0.69)
</td><td align="left" valign="top" rowspan="1" colspan="1">* >160</td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">SW1222 4 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">0.02
<break></break> (0.02 to 0.02)
</td><td align="left" valign="top" rowspan="1" colspan="1">1.19
<break></break> (0.76 to 1.91)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.61
<break></break> (0.43 to 0.87)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.04
<break></break> (0.02 to 0.07)
</td><td align="left" valign="top" rowspan="1" colspan="1">39.5
<break></break> (27.01-57.36)
</td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">HCA7 0 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">0.06
<break></break> (0.01 to 0.47)
</td><td align="left" valign="top" rowspan="1" colspan="1">2.37
<break></break> (1.76 to 3.26)
</td><td align="left" valign="top" rowspan="1" colspan="1">* >20</td><td align="left" valign="top" rowspan="1" colspan="1">0.41
<break></break> (0.21 to 0.89)
</td><td align="left" valign="top" rowspan="1" colspan="1">196.8
<break></break> (178.93 to 231)
</td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">HCA7 4 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">0.01
<break></break> (0.00 to 0.14)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.42
<break></break> (0.36 to 0.49)
</td><td align="left" valign="top" rowspan="1" colspan="1">*18.77</td><td align="left" valign="top" rowspan="1" colspan="1">0.15
<break></break> (0.09 to 0.24)
</td><td align="left" valign="top" rowspan="1" colspan="1">116.7
<break></break> (64.29 to 256.3)
</td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">HT55 0 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">0.06
<break></break> (0.05 to 0.09)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.97
<break></break> (0.73 to 1.28)
</td><td align="left" valign="top" rowspan="1" colspan="1">1.55
<break></break> (0.28 to 5.02)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.08
<break></break> (0.03 to 0.29)
</td><td align="left" valign="top" rowspan="1" colspan="1">49.39
<break></break> (15.7 to 169.4)
</td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">HT55 4 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">0.02
<break></break> (0.01 to 0.02)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.37
<break></break> (0.3 to 0.47)
</td><td align="left" valign="top" rowspan="1" colspan="1">1.55
<break></break> (0.41 to 3.33)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.05
<break></break> (0.03 to 0.09)
</td><td align="left" valign="top" rowspan="1" colspan="1">50.77
<break></break> (22.77 to 132)
</td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">C99 0 Gy</td><td align="left" valign="top" rowspan="1" colspan="1">0.12
<break></break> (0.07 to 0.22)
</td><td align="left" valign="top" rowspan="1" colspan="1">3.75
<break></break> (1.92 to 8.38)
</td><td align="left" valign="top" rowspan="1" colspan="1">1.27
<break></break> (0.32 to 5.5)
</td><td align="left" valign="top" rowspan="1" colspan="1">0.01
<break></break> (0.007 to 0.023)
</td><td align="left" valign="top" rowspan="1" colspan="1">* >160</td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td style="class:table_bottom_border" align="left" valign="top" rowspan="1" colspan="1">C99 4 Gy</td><td style="class:table_bottom_border" align="left" valign="top" rowspan="1" colspan="1">0.34
<break></break> (0.07 to 2.32)
</td><td style="class:table_bottom_border" align="left" valign="top" rowspan="1" colspan="1">1.43
<break></break> (0.32 to 7.72)
</td><td style="class:table_bottom_border" align="left" valign="top" rowspan="1" colspan="1">0.38
<break></break> (0.16 to 1.08)
</td><td style="class:table_bottom_border" align="left" valign="top" rowspan="1" colspan="1">0.004
<break></break> (0.002 to 0.007)
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