Abstract IA027: New advances in the pathogenesis of renal cell carcinoma in tuberous sclerosis and Birt-Hogg-Dubé syndrome

Abstract

Abstract Tuberous Sclerosis Complex (TSC) is caused by either TSC1 or TSC2 mutations, resulting in tumors of the brain, heart, skin, and kidney with hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1). Renal cell carcinomas (RCC) in TSC have chromophobe-like histology features. In TSC2-deficient cells, mTORC1 activity toward its canonical (Raptor-dependent) substrates is increased, while the phosphorylation of non-canonical substrates such as TFEB is decreased, leading to nuclear localization and increased activity of TFEB. Remarkably, treatment with the mTORC1 inhibitor Rapamycin or downregulation of Rheb or Raptor shifts the balance of mTORC1 activity toward the non-canonical substrates in TSC2-deficient cells, leading to increased phosphorylation of TFEB and decreased TFEB activity. Knockout of Tfeb abolishes renal pathology in two mouse models of TSC, indicating that this substrate specificity is the critical mediator of renal disease in TSC. Together, our results indicate that the TSC protein complex controls a critical switch in mTORC1 substrate specificity upstream of Rheb and the Rags, and the effects of rapamycin in TSC are mediated by the paradoxical increased activity of mTORC1 towards the non-canonical target TFEB. These findings may shed light on the sporadic form of chromophobe RCC, which is derived from the renal intercalated cells and has several mysterious features including mitochondrial abundance, whole chromosome losses, and high levels of glutathione (50-100 times higher than matched normal kidney). We hypothesize that hyperactivation of TFEB and/or TFE3 may represent a “missing link” to chromophobe RCC, which highly express lysosomal genes and proteins, thereby connecting chromophobe RCC to TSC-associated and BHD-associated RCC and to translocation RCC. Citation Format: Elizabeth Henske. New advances in the pathogenesis of renal cell carcinoma in tuberous sclerosis and Birt-Hogg-Dubé syndrome [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr IA027.