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Preprint WatchMildSeptember 29th, 2026

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

Xu, J.; Cheng, X.; Aboud, O. A.; Chen, Y.; Bialik, A.; Reznik, E.; Oyama, T.; Tickoo, S.; Weiss, R. H.; Cheng, E. H.; Hsieh, J. J.

A kidney-specific Vhl and Tsc1 double knockout mouse develops penetrant clear cell renal cell carcinoma, and NRF2 (NFE2L2) driven antioxidant signalling is proposed as a therapeutic vulnerability in human VHL and TSC1 null tumours.

Mild contradiction

1 prior failure

One documented clinical failure (Phase 1 or 2) overlaps with the claimed mechanism.

This preprint nominates NRF2 (NFE2L2) as a therapeutic vulnerability in VHL and TSC1 null clear cell renal cell carcinoma, supported by a penetrant mouse model plus transcriptomic, metabolomic and xenograft work. Claidex holds one NFE2L2 failure, mgy825-nfe2l2-nrf2-mutant-nsclc-phase1-strategic-termination, a Phase 1 programme in NFE2L2, KEAP1 or CUL3 mutant non-small cell lung cancer that ended in strategic termination rather than on efficacy or safety grounds. The severity here is MILD because a single prior failure with a portfolio archetype carries no evidence that the target itself does not work. The useful contrast is directional: the terminated programme targeted tumours with constitutive NRF2 pathway activation, while this preprint proposes an acquired NRF2 dependency arising downstream of HIF and mTORC1 activation, which is a different patient selection premise and would need its own biomarker definition.

Abstract excerpt

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.

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This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.