Therapeutic targeting of cellular metabolism in cells with hyperactive mTORC1: a paradigm shift

mTORC1 is an established master regulator of cellular metabolic homeostasis, via multiple mechanisms that include altered glucose and glutamine metabolism, and decreased autophagy. mTORC1 is hyperactive in the human disease tuberous sclerosis complex (TSC), an autosomal dominant disorder caused by germline mutations in the TSC1 or TSC2 gene. In TSC-deficient cells, metabolic wiring is extensively disrupted and rerouted as a consequence of mTORC1 hyperactivation, leading to multiple vulnerabilities, including "addiction" to glutamine, glucose, and autophagy. There is synergy between two rapidly evolving trajectories: elucidating the metabolic vulnerabilities of TSC-associated tumor cells, and the development of therapeutic agents that selectively target cancer-associated metabolic defects. The current review focuses on recent work supporting the targeting of cellular metabolic dysregulation for the treatment of tumors in TSC, with relevance to the many other human neoplasms with mTORC1 hyperactivation. These data expose a fundamental paradox in the therapeutic targeting of tumor cells with hyperactive mTORC1: inhibition of mTORC1 may not represent the optimal therapeutic strategy. Inhibiting mTORC1 "fixes" the metabolic vulnerabilities, results in a cytostatic response, and closes the door to metabolic targeting. In contrast, leaving mTORC1 active allows the metabolic vulnerabilities to be targeted with the potential for a cytocidal cellular response. The insights provided here suggest that therapeutic strategies for TSC and other tumors with activation of mTORC1 are at the verge of a major paradigm shift, in which optimal clinical responses will be accomplished by targeting mTORC1-associated metabolic vulnerabilities without inhibiting mTORC1 itself.