Molecular Medicine Israel

Unconventional mechanism of action and resistance to rapalogs in renal cancer


While rapalogs have been thought to function primarily by suppressing mTORC1 in kidney cancer cells, we show that mTORC1 inhibition of nontumor cells is essential for their antitumor activity. Furthermore, failure to inhibit mTORC1 in the tumor microenvironment (TME) confers resistance to rapalogs, highlighting a critical role of the TME. These findings offer an explanation for the lack of mTOR mutations in resistant tumors and open broad avenues for therapeutic interventions.


mTORC1 is aberrantly activated in renal cell carcinoma (RCC) and is targeted by rapalogs. As for other targeted therapies, rapalogs clinical utility is limited by the development of resistance. Resistance often results from target mutation, but mTOR mutations are rarely found in RCC. As in humans, prolonged rapalog treatment of RCC tumorgrafts (TGs) led to resistance. Unexpectedly, explants from resistant tumors became sensitive both in culture and in subsequent transplants in mice. Notably, resistance developed despite persistent mTORC1 inhibition in tumor cells. In contrast, mTORC1 became reactivated in the tumor microenvironment (TME). To test the role of the TME, we engineered immunocompromised recipient mice with a resistance mTOR mutation (S2035T). Interestingly, TGs became resistant to rapalogs in mTORS2035T mice. Resistance occurred despite mTORC1 inhibition in tumor cells and could be induced by coculturing tumor cells with mutant fibroblasts. Thus, enforced mTORC1 activation in the TME is sufficient to confer resistance to rapalogs. These studies highlight the importance of mTORC1 inhibition in nontumor cells for rapalog antitumor activity and provide an explanation for the lack of mTOR resistance mutations in RCC patients.

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