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mTOR inhibition attenuates chemosensitivity through the induction of chemotherapy resistant persisters

Liu, Yuanhui and Azizian, Nancy G. and Sullivan, Delaney K. and Li, Yulin (2022) mTOR inhibition attenuates chemosensitivity through the induction of chemotherapy resistant persisters. Nature Communications, 13 . Art. No. 7047. ISSN 2041-1723. PMCID PMC9671908. doi:10.1038/s41467-022-34890-6.

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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.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle
Azizian, Nancy G.0000-0002-1158-0608
Sullivan, Delaney K.0000-0002-8359-6705
Li, Yulin0000-0003-3479-9909
Additional Information:We thank Dr. Marina Pasca di Magliano for generously providing the 4292 murine pancreatic cancer cell line, Matthew Vasquez for assistance with confocal microscopy, Dr. Dawei Zou for help with flow cytometry, and Dr. Yael Rosenberg-Hasson for assistance with cytokine assays. This work was supported in part by NIH K22CA207598 (Y.Li.), CPRIT RP200472 (Y.Li.), and NIH T32GM008042 (D.K.S.; UCLA-Caltech Medical Scientist Training Program).
Funding AgencyGrant Number
Cancer Prevention and Research Institute of TexasRP200472
NIH Predoctoral FellowshipT32GM008042
UCLA-Caltech Medical Scientist Training ProgramUNSPECIFIED
PubMed Central ID:PMC9671908
Record Number:CaltechAUTHORS:20221202-907217500.13
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:118216
Deposited By: Research Services Depository
Deposited On:05 Jan 2023 16:55
Last Modified:05 Jan 2023 16:55

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