Combined Loss of VHL and TSC1 Drives Clear Cell Renal Cell Carcinoma with Metabolic and Redox Reprogramming that Creates an NRF2 Dependency

Cancer genomics studies have implicated combined loss of VHL and TSC1 as sufficient to initiate clear cell renal cell carcinoma (ccRCC) in humans. Here, we engineered a mouse model with kidney-specific deletion of Vhl and Tsc1. VhlF/FTsc1F/FKsp-Cre+ mice developed multifocal renal cell carcinomas starting at 7 weeks of age with 100% penetrance, and the resulting Vhl-/-Tsc1-/- tumors recapitulated the histopathology of human VHL-/-TSC1-/- ccRCC. Integrated transcriptomic and metabolomic analyses of 4-week-old preneoplastic renal cortices deficient for Vhl and Tsc1 demonstrated heightened HIF and mTORC1 signaling and unexpectedly revealed activation of an antioxidant response regulated by NRF2 (NFE2L2). Biochemical, cell biological, multi-omic, and xenograft studies identified an NRF2 dependency in human VHL-/-TSC1-/- ccRCC cells. Altogether, we report a mouse model that recapitulates human VHL-/-TSC1-/- ccRCC, delineate metabolic and redox reprogramming driven by unrestrained HIF and mTORC1 activation in the renal cortex, and identify NRF2 as a potential therapeutic vulnerability.