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Identification of anticancer drugs to radiosensitise BRAF-wild-type and mutant colorectal cancer
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 oncolo...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Chinese Anti-Cancer Association
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713640/ https://www.ncbi.nlm.nih.gov/pubmed/31516745 http://dx.doi.org/10.20892/j.issn.2095-3941.2018.0284 |
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author | Carter, Rebecca Cheraghchi-Bashi, Azadeh Westhorpe, Adam Yu, Sheng Shanneik, Yasmin Seraia, Elena Ouaret, Djamila Inoue, Yasuhiro Koch, Catherine Wilding, Jenny Ebner, Daniel Ryan, Anderson J. Buffa, Francesca M. Sharma, Ricky A. |
author_facet | Carter, Rebecca Cheraghchi-Bashi, Azadeh Westhorpe, Adam Yu, Sheng Shanneik, Yasmin Seraia, Elena Ouaret, Djamila Inoue, Yasuhiro Koch, Catherine Wilding, Jenny Ebner, Daniel Ryan, Anderson J. Buffa, Francesca M. Sharma, Ricky A. |
author_sort | Carter, Rebecca |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6713640 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Chinese Anti-Cancer Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-67136402019-09-12 Identification of anticancer drugs to radiosensitise BRAF-wild-type and mutant colorectal cancer Carter, Rebecca Cheraghchi-Bashi, Azadeh Westhorpe, Adam Yu, Sheng Shanneik, Yasmin Seraia, Elena Ouaret, Djamila Inoue, Yasuhiro Koch, Catherine Wilding, Jenny Ebner, Daniel Ryan, Anderson J. Buffa, Francesca M. Sharma, Ricky A. Cancer Biol Med Original Article 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. Chinese Anti-Cancer Association 2019-05 /pmc/articles/PMC6713640/ /pubmed/31516745 http://dx.doi.org/10.20892/j.issn.2095-3941.2018.0284 Text en Copyright 2019 Cancer Biology & Medicine http://creativecommons.org/licenses/by-nc-sa/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/ |
spellingShingle | Original Article Carter, Rebecca Cheraghchi-Bashi, Azadeh Westhorpe, Adam Yu, Sheng Shanneik, Yasmin Seraia, Elena Ouaret, Djamila Inoue, Yasuhiro Koch, Catherine Wilding, Jenny Ebner, Daniel Ryan, Anderson J. Buffa, Francesca M. Sharma, Ricky A. Identification of anticancer drugs to radiosensitise BRAF-wild-type and mutant colorectal cancer |
title | Identification of anticancer drugs to radiosensitise BRAF-wild-type and mutant colorectal cancer
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title_full | Identification of anticancer drugs to radiosensitise BRAF-wild-type and mutant colorectal cancer
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title_fullStr | Identification of anticancer drugs to radiosensitise BRAF-wild-type and mutant colorectal cancer
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title_full_unstemmed | Identification of anticancer drugs to radiosensitise BRAF-wild-type and mutant colorectal cancer
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title_short | Identification of anticancer drugs to radiosensitise BRAF-wild-type and mutant colorectal cancer
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title_sort | identification of anticancer drugs to radiosensitise braf-wild-type and mutant colorectal cancer |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713640/ https://www.ncbi.nlm.nih.gov/pubmed/31516745 http://dx.doi.org/10.20892/j.issn.2095-3941.2018.0284 |
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