Journal
BRITISH JOURNAL OF CANCER
Volume 123, Issue 12, Pages 1749-1756Publisher
SPRINGERNATURE
DOI: 10.1038/s41416-020-01087-x
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Funding
- National Institutes of Health [R03 CA216173, R03 CA246011, R21 CA223394, R03 CA212949, R03 CA235060]
- Department of Defense Idea Development Award [KC170127]
- NCI Core Grant [NCI P30 CA006927]
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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.
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