Abstract
BackgroundMulti-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.MethodsWe 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.ResultsOur 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.ConclusionCRISPR/Cas9 LOF screening presents a promising approach to identify and target cellular factors involved in the resistance to anti-cancer therapeutics.
Highlights
Multi-targeted tyrosine kinase inhibitors (TKIs) are the standard of care for patients with advanced clear cell renal cell carcinoma
CRISPR/Cas9-based genome-wide loss of function (LOF) screening to identify cellular factors contributing to sunitinib resistance in clear cell renal cell carcinoma (ccRCC) To identify cellular factors involved in sunitinib resistance, we infected 786-O ccRCC cells with human CRISPR sgRNA library as described in Methods
To further define the mechanism of lonafarnibmediated sensitisation of tumour cells to sunitinib, we examined whether the lysosomal sequestration of sunitinib can be disrupted by lonafarnib
Summary
Multi-targeted tyrosine kinase inhibitors (TKIs) are the standard of care for patients with advanced clear cell renal cell carcinoma (ccRCC). Renal cell carcinoma (RCC) is the most common type of kidney cancer with rising incidence.[1] It is categorised into various subtypes, with clear cell RCC (ccRCC) representing ~85% of all RCC tumours.[2] Papillary RCC and chromophobe RCC represent the most common remaining histologic subtypes with an incidence of 7–14% and 6–11%, respectively.[2] Current targeted molecular strategies, including multitargeted tyrosine kinase inhibitors (TKIs), have resulted in a doubling of progression-free survival and significant gains in overall survival, thereby notably changing the treatment paradigm of advanced kidney cancer.[3,4] Yet, about onequarter of the ccRCC patients are primarily refractory to treatment with TKIs.[5] most patients that respond initially will typically progress within 12 months of starting therapy.[6]
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