mTOR inhibition attenuates chemosensitivity through the induction of chemotherapy resistant persisters

Yuanhui Liu, Nancy G. Azizian, Delaney K. Sullivan and Yulin Li ()
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Yuanhui Liu: Houston Methodist Research Institute
Nancy G. Azizian: Houston Methodist Research Institute
Delaney K. Sullivan: University of California, Los Angeles
Yulin Li: Houston Methodist Research Institute

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract Chemotherapy can eradicate a majority of cancer cells. However, a small population of tumor cells often survives drug treatments through genetic and/or non-genetic mechanisms, leading to tumor recurrence. Here we report a reversible chemoresistance phenotype regulated by the mTOR pathway. Through a genome-wide CRISPR knockout library screen in pancreatic cancer cells treated with chemotherapeutic agents, we have identified the mTOR pathway as a prominent determinant of chemosensitivity. Pharmacological suppression of mTOR activity in cancer cells from diverse tissue origins leads to the persistence of a reversibly resistant population, which is otherwise eliminated by chemotherapeutic agents. Conversely, activation of the mTOR pathway increases chemosensitivity in vitro and in vivo and predicts better survival among various human cancers. Persister cells display a senescence phenotype. Inhibition of mTOR does not induce cellular senescence per se, but rather promotes the survival of senescent cells through regulation of autophagy and G2/M cell cycle arrest, as revealed by a small-molecule chemical library screen. Thus, mTOR plays a causal yet paradoxical role in regulating chemotherapeutic response; inhibition of the mTOR pathway, while suppressing tumor expansion, facilitates the development of a reversible drug-tolerant senescence state.

Date: 2022
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DOI: 10.1038/s41467-022-34890-6

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