Identification of anticancer drugs to radiosensitise <i>BRAF</i>-wild-type and mutant colorectal cancer

Cancer Biology & Medicine. 2019;16(2):234-246 DOI 10.20892/j.issn.2095-3941.2018.0284

 

Journal Homepage

Journal Title: Cancer Biology & Medicine

ISSN: 2095-3941 (Print)

Publisher: China Anti-Cancer Association

LCC Subject Category: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens

Country of publisher: China

Language of fulltext: English

Full-text formats available: PDF, HTML

 

AUTHORS


Rebecca Carter (NIHR University College London Hospitals Biomedical Research Centre, UCL Cancer Institute, University College London, London WC1E 6DD, UK)

Azadeh Cheraghchi-Bashi

Adam Westhorpe (NIHR University College London Hospitals Biomedical Research Centre, UCL Cancer Institute, University College London, London WC1E 6DD, UK)

Sheng Yu (Computational Biology and Integrative Genomics, University of Oxford, Oxford OX1 2JD, UK)

Yasmin Shanneik (NIHR Oxford Biomedical Research Centre, Department of Oncology, University of Oxford, Oxford OX1 2JD, UK)

Elena Seraia (NDM Research Building, Nuffield Department of Medicine, University of Oxford, Oxford OX1 2JD, UK)

Djamila Ouaret (Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX1 2JD, UK)

Yasuhiro Inoue (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)

Catherine Koch (Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA)

Jenny Wilding (Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX1 2JD, UK)

Daniel Ebner (Target Discovery Institute, National Phenotypic Screening Centre, Nuffield Department of Medicine, University of Oxford, Oxford OX1 2JD, UK)

Anderson J. Ryan (CRUK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX1 2JD, UK)

Francesca M. Buffa (CRUK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX1 2JD, UK)

Ricky A. Sharma (NIHR University College London Hospitals Biomedical Research Centre, UCL Cancer Institute, University College London, London WC1E 6DD, UK)

EDITORIAL INFORMATION

Blind peer review

Editorial Board

Instructions for authors

Time From Submission to Publication: 12 weeks

 

Abstract | Full Text

<b>Objective</b> Patients with <i>BRAF</i>-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 <i>BRAF</i> status.<b>Methods</b> We screened 298 oncological drugs with and without ionising radiation in colorectal cancer cells isogenic for <i>BRAF</i>. 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 <i>in vivo</i>.<b>Results</b> 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 (<i>BRAF</i>-wildtype) cells and 1.8 in RKO (<i>BRAF</i> V600E) cells. In DLD1 xenografts, talazoparib significantly increased the inhibitory effect of radiation on tumour growth (<i>P</i> ≤ 0.01). <b>Conclusions</b> 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 <i>BRAF</i> backgrounds.