TY - JOUR
T1 - CRISPR/Cas9 genome-wide loss-of-function screening identifies druggable cellular factors involved in sunitinib resistance in renal cell carcinoma
AU - Makhov, Peter
AU - Sohn, Ji A.
AU - Serebriiskii, Ilya G.
AU - Fazliyeva, Rushaniya
AU - Khazak, Vladimir
AU - Boumber, Yanis
AU - Uzzo, Robert G.
AU - Kolenko, Vladimir M.
N1 - Funding Information:
The CRISPR sgRNA library was a gift of Dr. Christoph Seeger (Fox Chase Cancer Center). The authors acknowledge the following Facilities at Fox Chase Cancer Center for their contributions to this work: Flow Cytometry, Laboratory Animal and High Throughput Screening (HTS, Dr. Margret Einarson, supported by R50 CA211479).
Funding Information:
Funding information This work was supported in part by the National Institutes of Health Grants R03 CA216173 and R03 CA246011 (to P.M.); R21 CA223394 (to Y.B. and P.M.); R03 CA212949 and R03 CA235060 (to V.M.K.), the Department of Defense Idea Development Award KC170127 (to V.M.K.), and the NCI Core Grant NCI P30 CA006927 (to Fox Chase Cancer Center).
PY - 2020/12/8
Y1 - 2020/12/8
N2 - 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.
AB - 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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U2 - 10.1038/s41416-020-01087-x
DO - 10.1038/s41416-020-01087-x
M3 - Article
C2 - 32968206
AN - SCOPUS:85091393508
VL - 123
SP - 1749
EP - 1756
JO - British Journal of Cancer
JF - British Journal of Cancer
SN - 0007-0920
IS - 12
ER -