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.
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.
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.
CRISPR/Cas9 LOF screening presents a promising approach to identify and target cellular factors involved in the resistance to anti-cancer therapeutics.
British journal of cancer. 2020 Sep 24 [Epub ahead of print]
Peter Makhov, Ji A Sohn, Ilya G Serebriiskii, Rushaniya Fazliyeva, Vladimir Khazak, Yanis Boumber, Robert G Uzzo, Vladimir M Kolenko
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, USA. ., Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, USA., Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, USA., Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA., Priaxon Inc., Philadelphia, PA, USA., Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA., Division of Urologic Oncology, Department of Surgery, Fox Chase Cancer Center, Philadelphia, PA, USA.