Identification of anticancer drugs to radiosensitise BRAF-wild-type and mutant colorectal cancer
Identifieur interne : 000A24 ( Ncbi/Merge ); précédent : 000A23; suivant : 000A25Identification of anticancer drugs to radiosensitise BRAF-wild-type and mutant colorectal cancer
Auteurs : Rebecca Carter [Royaume-Uni] ; Azadeh Cheraghchi-Bashi [Royaume-Uni] ; Adam Westhorpe [Royaume-Uni] ; Sheng Yu [Royaume-Uni] ; Yasmin Shanneik [Royaume-Uni] ; Elena Seraia [Royaume-Uni] ; Djamila Ouaret [Royaume-Uni] ; Yasuhiro Inoue [Japon] ; Catherine Koch [États-Unis] ; Jenny Wilding [Royaume-Uni] ; Daniel Ebner [Royaume-Uni] ; Anderson J. Ryan [Royaume-Uni] ; Francesca M. Buffa [Royaume-Uni] ; Ricky A. Sharma [Royaume-Uni]Source :
- 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
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<author><name sortKey="Ryan, Anderson J" sort="Ryan, Anderson J" uniqKey="Ryan A" first="Anderson J." last="Ryan">Anderson J. Ryan</name>
<affiliation wicri:level="4"><nlm:aff id="aff9"><addr-line>CRUK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX1 2JD, UK</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>CRUK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX1 2JD</wicri:regionArea>
<orgName type="university">Université d'Oxford</orgName>
<placeName><settlement type="city">Oxford</settlement>
<region type="nation">Angleterre</region>
<region type="région" nuts="1">Oxfordshire</region>
</placeName>
</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 wicri:level="4"><nlm:aff id="aff9"><addr-line>CRUK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX1 2JD, UK</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>CRUK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX1 2JD</wicri:regionArea>
<orgName type="university">Université d'Oxford</orgName>
<placeName><settlement type="city">Oxford</settlement>
<region type="nation">Angleterre</region>
<region type="région" nuts="1">Oxfordshire</region>
</placeName>
</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 wicri:level="1"><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>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>NIHR University College London Hospitals Biomedical Research Centre, UCL Cancer Institute, University College London, London WC1E 6DD</wicri:regionArea>
<wicri:noRegion>London WC1E 6DD</wicri:noRegion>
</affiliation>
<affiliation wicri:level="4"><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>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>NIHR Oxford Biomedical Research Centre, Department of Oncology, University of Oxford, Oxford OX1 2JD</wicri:regionArea>
<orgName type="university">Université d'Oxford</orgName>
<placeName><settlement type="city">Oxford</settlement>
<region type="nation">Angleterre</region>
<region type="région" nuts="1">Oxfordshire</region>
</placeName>
</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>
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</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>
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<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>
</pmc>
<affiliations><list><country><li>Japon</li>
<li>Royaume-Uni</li>
<li>États-Unis</li>
</country>
<region><li>Angleterre</li>
<li>Oxfordshire</li>
</region>
<settlement><li>Oxford</li>
</settlement>
<orgName><li>Université d'Oxford</li>
</orgName>
</list>
<tree><country name="Royaume-Uni"><noRegion><name sortKey="Carter, Rebecca" sort="Carter, Rebecca" uniqKey="Carter R" first="Rebecca" last="Carter">Rebecca Carter</name>
</noRegion>
<name sortKey="Buffa, Francesca M" sort="Buffa, Francesca M" uniqKey="Buffa F" first="Francesca M." last="Buffa">Francesca M. Buffa</name>
<name sortKey="Carter, Rebecca" sort="Carter, Rebecca" uniqKey="Carter R" first="Rebecca" last="Carter">Rebecca Carter</name>
<name sortKey="Cheraghchi Bashi, Azadeh" sort="Cheraghchi Bashi, Azadeh" uniqKey="Cheraghchi Bashi A" first="Azadeh" last="Cheraghchi-Bashi">Azadeh Cheraghchi-Bashi</name>
<name sortKey="Ebner, Daniel" sort="Ebner, Daniel" uniqKey="Ebner D" first="Daniel" last="Ebner">Daniel Ebner</name>
<name sortKey="Ouaret, Djamila" sort="Ouaret, Djamila" uniqKey="Ouaret D" first="Djamila" last="Ouaret">Djamila Ouaret</name>
<name sortKey="Ryan, Anderson J" sort="Ryan, Anderson J" uniqKey="Ryan A" first="Anderson J." last="Ryan">Anderson J. Ryan</name>
<name sortKey="Seraia, Elena" sort="Seraia, Elena" uniqKey="Seraia E" first="Elena" last="Seraia">Elena Seraia</name>
<name sortKey="Shanneik, Yasmin" sort="Shanneik, Yasmin" uniqKey="Shanneik Y" first="Yasmin" last="Shanneik">Yasmin Shanneik</name>
<name sortKey="Sharma, Ricky A" sort="Sharma, Ricky A" uniqKey="Sharma R" first="Ricky A." last="Sharma">Ricky A. Sharma</name>
<name sortKey="Sharma, Ricky A" sort="Sharma, Ricky A" uniqKey="Sharma R" first="Ricky A." last="Sharma">Ricky A. Sharma</name>
<name sortKey="Westhorpe, Adam" sort="Westhorpe, Adam" uniqKey="Westhorpe A" first="Adam" last="Westhorpe">Adam Westhorpe</name>
<name sortKey="Westhorpe, Adam" sort="Westhorpe, Adam" uniqKey="Westhorpe A" first="Adam" last="Westhorpe">Adam Westhorpe</name>
<name sortKey="Wilding, Jenny" sort="Wilding, Jenny" uniqKey="Wilding J" first="Jenny" last="Wilding">Jenny Wilding</name>
<name sortKey="Yu, Sheng" sort="Yu, Sheng" uniqKey="Yu S" first="Sheng" last="Yu">Sheng Yu</name>
</country>
<country name="Japon"><noRegion><name sortKey="Inoue, Yasuhiro" sort="Inoue, Yasuhiro" uniqKey="Inoue Y" first="Yasuhiro" last="Inoue">Yasuhiro Inoue</name>
</noRegion>
</country>
<country name="États-Unis"><noRegion><name sortKey="Koch, Catherine" sort="Koch, Catherine" uniqKey="Koch C" first="Catherine" last="Koch">Catherine Koch</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>
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