CRISPR/Cas9 genome-wide loss-of-function screening identifies druggable cellular factors involved in sunitinib resistance in renal cell carcinoma

Peter Makhov*, Ji A. Sohn, Ilya G. Serebriiskii, Rushaniya Fazliyeva, Vladimir Khazak, Yanis Boumber, Robert G. Uzzo, Vladimir M. Kolenko

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1749-1756
Number of pages8
JournalBritish Journal of Cancer
Volume123
Issue number12
DOIs
StatePublished - Dec 8 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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