Functional roles of mTOR in tumor persistence

PROJECT SUMMARY The mTOR pathway is a master regulator of nutrient metabolism and cell proliferation in response to environmental cues. It has long been viewed as an important driver of tumorigenesis and an ideal cancer therapeutic target. Multiple mTOR inhibitors have been tested in more than 500 clinical trials, either as single agents or in combination with chemotherapy for cancer treatment. However, among nearly 200 completed trials, few show positive outcomes, challenging the utility of mTOR as an effective cancer therapeutic target. As an integrator of extracellular signals and cellular responses, the mTOR pathway is critical for cellular adaptation to environmental changes. In particular, mTOR inhibition induces embryonic diapause, a reversible dormancy state in development in response to unfavorable environment cues. We reason that, analogous to its role in embryonic diapause, mTOR inhibition may induce an adaptive diapause-like dormant state in cancers, leading to the persistence of residual tumors following chemotherapy. In line with this notion, recent studies have indeed reported markedly reduced mTOR activity in residual tumors. However, a causal relationship between mTOR inhibition and tumor persistence has not been established or investigated. Integrating multiple state-of-the-art approaches, our recent studies show that mTOR inhibition indeed induces a diapause-like persister state in tumor cells. We confirm that this is a pan-cancer phenomenon using tumors from diverse tissue origins and demonstrate that the persister state recapitulates the residual tumors in patients following chemotherapy. Importantly, our studies identify ferroptosis as a key druggable vulnerability of persisters. Built on these compelling findings, we hypothesize that mTOR is a master regulator of a diapause-like persister state in tumors by modulating survival and dormancy. The current proposal aims to investigate the mechanistic regulation of the persister state, and test therapeutic strategies to target residual tumors in preclinical models, with the ultimate goal to prevent tumor recurrence in patients.