Abstract Cancer genomics implicated that combined genetic losses of VHL and TSC1 are sufficient to initiate clear cell renal cell carcinoma (ccRCC) in human. Here, we engineered a mouse model with kidney-specific deletion of Vhl and Tsc1. Vhl-/-Tsc1-/- mice developed multifocal renal cell carcinoma starting at 7 weeks of age with 100% penetrance. These Vhl-/-Tsc1-/- mouse kidney tumors mimicked the histopathology of human VHL-/-TSC1-/- kidney tumors. Integrated transcriptomic and metabolomic analyses of 4-week-old precancerous mouse kidney cortex demonstrated that Vhl-/-Tsc1-/- kidney cells not only exhibit heightened HIF and mTORC1 signals but also engage antioxidant response regulated by the Nuclear factor erythroid 2-related factor 2 (NFE2L2 or NRF2). Biochemical, cell biological, cancer multi-omic, and xenograft studies discovered NRF2-dependence in human VHL-/-TSC1-/- ccRCC cells. Altogether, we report a mouse model recapitulating human VHL-/-TSC1-/- ccRCC, delineate metabolic/redox reprogramming upon unbridled HIF and mTORC1 activation in the kidney cortex, and present unique therapeutic opportunities. Citation Format: Xiaoqing (Cathy) Cheng, Jianing Xu, Omran Abu Aboud, Ying-Bei Chen, Ed Reznik, Toshinao Oyama, Satish Tickoo, Emily H. Cheng, Robert H. Weiss, James J. Hsieh. Vhl-/-Tsc1-/-mice rapidly develop clear cell renal cell carcinoma with pronounced metabolic and redox reprogramming that necessitates NRF2 signaling abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB294.
Cheng et al. (2026) studied this question.