Identification of anticancer drugs to radiosensitise BRAF -wild-type and mutant colorectal cancer

Patients with -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 status. We screened 298 oncological drugs with and without...

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Published in:Cancer biology & medicine Vol. 16; no. 2; pp. 234 - 246
Main Authors: 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. Sharma
Format: Journal Article
Language:English
Published: China NIHR University College London Hospitals Biomedical Research Centre, UCL Cancer Institute, University College London, London WC1E 6DD, UK 01.05.2019
NIHR Oxford Biomedical Research Centre, Department of Oncology, University of Oxford, Oxford OX12JD, UK%NIHR Oxford Biomedical Research Centre, Department of Oncology, University of Oxford, Oxford OX12JD, UK%Computational Biology and Integrative Genomics, University of Oxford, Oxford OX12JD, UK%NDM Research Building, Nuffield Department of Medicine, University of Oxford, Oxford OX12JD, UK%Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX12JD, UK%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%Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA%Target Discovery Institute, National Phenotypic Screening Centre, Nuffield Department of Medicine, University of Oxford, Oxford OX12JD, UK%CRUK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX12JD, UK
Chinese Anti-Cancer Association
China Anti-Cancer Association
Subjects:
colorectal cancer
Original
PARP inhibitor
Radiosensitizer
radiotherapy
radiotherapy
Radiosensitizer
colorectal cancer
PARP inhibitor
ISSN:2095-3941, 2095-3941
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Summary:Patients with -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 status. We screened 298 oncological drugs with and without ionising radiation in colorectal cancer cells isogenic for . 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 . 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 ( -wildtype) cells and 1.8 in RKO ( V600E) cells. In DLD1 xenografts, talazoparib significantly increased the inhibitory effect of radiation on tumour growth ( ≤ 0.01). 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 backgrounds.
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These authors contributed equally to this work.
ISSN:2095-3941
2095-3941
DOI:10.20892/j.issn.2095-3941.2018.0284