Identification of anticancer drugs to radiosensitise BRAF-wild-type and mutant colorectal cancer
Identifieur interne : 000759 ( Main/Exploration ); précédent : 000758; suivant : 000760Identification 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
Affiliations:
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2JD, UK</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>NDM Research Building, Nuffield Department of Medicine, 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="Ouaret, Djamila" sort="Ouaret, Djamila" uniqKey="Ouaret D" first="Djamila" last="Ouaret">Djamila Ouaret</name><affiliation wicri:level="4"><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><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX1 2JD</wicri:regionArea><orgName type="university">Université 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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. 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</title><author><name sortKey="Carter, Rebecca" sort="Carter, Rebecca" uniqKey="Carter R" first="Rebecca" last="Carter">Rebecca Carter</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><author><name sortKey="Cheraghchi Bashi, Azadeh" sort="Cheraghchi Bashi, Azadeh" uniqKey="Cheraghchi Bashi A" first="Azadeh" last="Cheraghchi-Bashi">Azadeh Cheraghchi-Bashi</name><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><author><name sortKey="Westhorpe, Adam" sort="Westhorpe, Adam" uniqKey="Westhorpe A" first="Adam" last="Westhorpe">Adam Westhorpe</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><author><name sortKey="Yu, Sheng" sort="Yu, Sheng" uniqKey="Yu S" first="Sheng" last="Yu">Sheng Yu</name><affiliation wicri:level="4"><nlm:aff id="aff3"><addr-line>Computational Biology and Integrative Genomics, University of Oxford, Oxford OX1 2JD, UK</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Computational Biology and Integrative Genomics, 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="Shanneik, Yasmin" sort="Shanneik, Yasmin" uniqKey="Shanneik Y" first="Yasmin" last="Shanneik">Yasmin Shanneik</name><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><author><name sortKey="Seraia, Elena" sort="Seraia, Elena" uniqKey="Seraia E" first="Elena" last="Seraia">Elena Seraia</name><affiliation wicri:level="4"><nlm:aff id="aff4"><addr-line>NDM Research Building, Nuffield Department of Medicine, University of Oxford, Oxford OX1 2JD, UK</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>NDM Research Building, Nuffield Department of Medicine, 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="Ouaret, Djamila" sort="Ouaret, Djamila" uniqKey="Ouaret D" first="Djamila" last="Ouaret">Djamila Ouaret</name><affiliation wicri:level="4"><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><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, 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="Inoue, Yasuhiro" sort="Inoue, Yasuhiro" uniqKey="Inoue Y" first="Yasuhiro" last="Inoue">Yasuhiro Inoue</name><affiliation wicri:level="1"><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><country xml:lang="fr">Japon</country><wicri:regionArea>Mie University, Graduate School of Medicine, Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Edobashi 2-174, Tsu</wicri:regionArea><wicri:noRegion>Tsu</wicri:noRegion></affiliation></author><author><name sortKey="Koch, Catherine" sort="Koch, Catherine" uniqKey="Koch C" first="Catherine" last="Koch">Catherine Koch</name><affiliation wicri:level="1"><nlm:aff id="aff7"><addr-line>Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142</wicri:regionArea><wicri:noRegion>Massachusetts 02142</wicri:noRegion></affiliation></author><author><name sortKey="Wilding, Jenny" sort="Wilding, Jenny" uniqKey="Wilding J" first="Jenny" last="Wilding">Jenny Wilding</name><affiliation wicri:level="4"><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><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, 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="Ebner, Daniel" sort="Ebner, Daniel" uniqKey="Ebner D" first="Daniel" last="Ebner">Daniel Ebner</name><affiliation wicri:level="4"><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><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Target Discovery Institute, National Phenotypic Screening Centre, Nuffield Department of Medicine, 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="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></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><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>Pour manipuler ce document sous Unix (Dilib)
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