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Kaushal Asrani, M.B.B.S., Ph.D.
Kaushal Asrani, M.B.B.S., Ph.D.

Deciphering Clues About mTORC1 Regulation May Identify Mediators of Kidney Tumorigenesis

Recently, our team uncovered a novel mechanism of tumor formation in kidney cancers driven by bi-allelic inactivation of the tuberous sclerosis complex (TSC) tumor suppressor genes, TSC1 and TSC2. Un-opposed mTORC1 signaling is a hallmark feature of renal tumors with TSC loss and pulmonary lymphangioleiomyomatosis (LAM), and is also observed in subsets of kidney and soft tissue tumors driven by gene fusions involving the TFEB/TFE3 transcription factors (“MiT family translocation neoplasms”). In this study we showed that non-canonical mTORC1 signaling involving phosphorylation of atypical substrates like TFEB and TFE3 was strikingly decreased in renal tumors with TSC loss, resulting in their constitutive activation. These effects were driven by impaired lysosomal recruitment and activity of the FLCN:FNIP2 complex proteins that are critical for mTORC1 activation at the lysosome. Consequently, dual genomic deletion of TFEB and TFEB or pharmacological inactivation of both factors by rapamycin, was sufficient to regress xenograft growth of these tumors. These findings suggest that that targeting the MiT/TFE pathway might potentially synergize with mTORC1 inhibitor therapy and point to a new approach for treating kidney cancers or other tumor types with overactive mTOR.

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