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.
Proceedings of the National Academy of Sciences of the United States of America. 2024 Jun 11 [Epub]
Juan Yang, Ramesh Butti, Shannon Cohn, Vanina Toffessi-Tcheuyap, Arijit Mal, Mylinh Nguyen, Christina Stevens, Alana Christie, Akhilesh Mishra, Yuanqing Ma, Jiwoong Kim, Robert Abraham, Payal Kapur, Robert E Hammer, James Brugarolas
Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390-8852., Department of Pediatrics, Dell Medical School, University of Texas at Austin, Austin, TX 78723., Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-8816., Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX 75390-8821., Oncology R&D Group, Pfizer Worldwide Research and Development, San Diego, CA 92121.