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mTOR inhibition attenuates chemosensitivity through the induction of chemotherapy resistant persisters

Author

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  • Yuanhui Liu

    (Houston Methodist Research Institute
    Weill Cornell Medical College)

  • Nancy G. Azizian

    (Houston Methodist Research Institute
    Weill Cornell Medical College)

  • Delaney K. Sullivan

    (University of California, Los Angeles)

  • Yulin Li

    (Houston Methodist Research Institute
    Weill Cornell Medical College)

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.

Suggested Citation

  • Yuanhui Liu & Nancy G. Azizian & Delaney K. Sullivan & Yulin Li, 2022. "mTOR inhibition attenuates chemosensitivity through the induction of chemotherapy resistant persisters," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34890-6
    DOI: 10.1038/s41467-022-34890-6
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    1. Yilei Zhang & Robert V. Swanda & Litong Nie & Xiaoguang Liu & Chao Wang & Hyemin Lee & Guang Lei & Chao Mao & Pranavi Koppula & Weijie Cheng & Jie Zhang & Zhenna Xiao & Li Zhuang & Bingliang Fang & Ju, 2021. "mTORC1 couples cyst(e)ine availability with GPX4 protein synthesis and ferroptosis regulation," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    2. Aydan Bulut-Karslioglu & Steffen Biechele & Hu Jin & Trisha A. Macrae & Miroslav Hejna & Marina Gertsenstein & Jun S. Song & Miguel Ramalho-Santos, 2016. "Inhibition of mTOR induces a paused pluripotent state," Nature, Nature, vol. 540(7631), pages 119-123, December.
    3. Hui-Ju Hsieh & Wei Zhang & Shu-Hong Lin & Wen-Hao Yang & Jun-Zhong Wang & Jianfeng Shen & Yiran Zhang & Yiling Lu & Hua Wang & Jane Yu & Gordon B. Mills & Guang Peng, 2018. "Systems biology approach reveals a link between mTORC1 and G2/M DNA damage checkpoint recovery," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
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    Cited by:

    1. Hyeong-Min Lee & William C. Wright & Min Pan & Jonathan Low & Duane Currier & Jie Fang & Shivendra Singh & Stephanie Nance & Ian Delahunty & Yuna Kim & Richard H. Chapple & Yinwen Zhang & Xueying Liu , 2023. "A CRISPR-drug perturbational map for identifying compounds to combine with commonly used chemotherapeutics," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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