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CRISPR/Cas9 genome-wide loss-of-function screening identifies druggable cellular factors involved in sunitinib resistance in renal cell carcinoma
Br J Cancer. 2020 Dec;123(12) :1749-1756
PMID: 32968206    PMCID: PMC7723036    URL: https://www.ncbi.nlm.nih.gov/pubmed/32968206
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Abstract
BACKGROUND: Multi-targeted tyrosine kinase inhibitors (TKIs) are the standard of care for patients with advanced clear cell renal cell carcinoma (ccRCC). However, a significant number of ccRCC patients are primarily refractory to targeted therapeutics, showing neither disease stabilisation nor clinical benefits. METHODS: We used CRISPR/Cas9-based high-throughput loss of function (LOF) screening to identify cellular factors involved in the resistance to sunitinib. Next, we validated druggable molecular factors that are synthetically lethal with sunitinib treatment using cell and animal models of ccRCC. RESULTS: Our screening identified farnesyltransferase among the top hits contributing to sunitinib resistance in ccRCC. Combined treatment with farnesyltransferase inhibitor lonafarnib potently augmented the anti-tumour efficacy of sunitinib both in vitro and in vivo. CONCLUSION: CRISPR/Cas9 LOF screening presents a promising approach to identify and target cellular factors involved in the resistance to anti-cancer therapeutics.
Notes
1532-1827 Makhov, Peter Orcid: 0000-0002-8257-4782 Sohn, Ji A Serebriiskii, Ilya G Fazliyeva, Rushaniya Khazak, Vladimir Boumber, Yanis Uzzo, Robert G Kolenko, Vladimir M CA216173/U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ CA246011/U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ CA223394/U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ CA212949/U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ CA235060/U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ KC170127/U.S. Department of Defense (United States Department of Defense)/ Journal Article England Br J Cancer. 2020 Dec;123(12):1749-1756. doi: 10.1038/s41416-020-01087-x. Epub 2020 Sep 24.