Interrogation of Genetic Dependencies in Renal Cell Carcinomas.

Division Of Basic Sciences - Nci

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Abstract

We have established a Cas9-Cas12a CHyMErA-based combinatorial CRISPR screening platform in patient-derived renal cell carcinoma (RCC) cell lines and confirmed robust nuclease expression and genome editing efficiency. Leveraging a genome-wide CRISPR knockout library, we conducted systematic screens across diverse environmental and genetic RCC contexts. This comprehensive approach revealed distinct metabolic dependencies that may serve as actionable therapeutic targets. Ongoing validation efforts are focused on confirming screen hits, elucidating the underlying molecular mechanisms influencing cell fitness, and assessing the conservation of these vulnerabilities across additional RCC models and other cancer types. In parallel, we are conducting chemogenetic screens to uncover genetic modifiers that modulate sensitivity to small-molecule inhibitors targeting these metabolic dependencies.