mTOR inhibition attenuates chemosensitivity through the induction of chemotherapy resistant persisters

• DOI: 10.1038/s41467-022-34890-6
• Publication Date: 2022-11-17T21:02:36Z
• Authors: Yuanhui Liu; Nancy G. Azizian; Delaney K. Sullivan; Yulin Li
• Keywords: 570; 0303 health sciences; Multidisciplinary; Science; TOR Serine-Threonine Kinases; Q; General Physics and Astronomy; 610; Genetics and Molecular Biology; General Chemistry; Article; 3. Good health; 03 medical and health sciences; Neoplasms; General Biochemistry; Autophagy; Humans; Cellular Senescence; Cell Proliferation

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