Identification of anticancer drugs to radiosensitise BRAF-wild-type and mutant colorectal cancer
Identifieur interne : 000A24 ( Ncbi/Curation ); 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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<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>
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