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

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

doi:10.20892/j.issn.2095-3941.2018.0284

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

Cancer Biol Med. 2019 May;16(2):234-246. doi: 10.20892/j.issn.2095-3941.2018.0284.

Authors

Rebecca Carter^{1

2}, Azadeh Cheraghchi-Bashi², Adam Westhorpe^{1

2}, Sheng Yu³, Yasmin Shanneik², Elena Seraia⁴, Djamila Ouaret⁵, Yasuhiro Inoue⁶, Catherine Koch⁷, Jenny Wilding⁵, Daniel Ebner⁸, Anderson J Ryan⁹, Francesca M Buffa⁹, Ricky A Sharma^{1

2}

Affiliations

¹ NIHR University College London Hospitals Biomedical Research Centre, UCL Cancer Institute, University College London, London WC1E 6DD, UK.
² NIHR Oxford Biomedical Research Centre, Department of Oncology, University of Oxford, Oxford OX1 2JD, UK.
³ Computational Biology and Integrative Genomics, University of Oxford, Oxford OX1 2JD, UK.
⁴ NDM Research Building, Nuffield Department of Medicine, University of Oxford, Oxford OX1 2JD, UK.
⁵ Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX1 2JD, UK.
⁶ 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.
⁷ Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
⁸ Target Discovery Institute, National Phenotypic Screening Centre, Nuffield Department of Medicine, University of Oxford, Oxford OX1 2JD, UK.
⁹ CRUK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX1 2JD, UK.

PMID: 31516745
PMCID: PMC6713640
DOI: 10.20892/j.issn.2095-3941.2018.0284

Abstract

Objective: Patients with BRAF-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 BRAF status.

Methods: We screened 298 oncological drugs with and without ionising radiation in colorectal cancer cells isogenic for BRAF. 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 in vivo.

Results: 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 (BRAF-wildtype) cells and 1.8 in RKO (BRAF V600E) cells. In DLD1 xenografts, talazoparib significantly increased the inhibitory effect of radiation on tumour growth (P ≤ 0.01).

Conclusions: 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 BRAF backgrounds.

Keywords: PARP inhibitor; Radiosensitizer; colorectal cancer; radiotherapy.

Abstract

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