A Novel mTORC1/2 Inhibitor (MTI-31) Inhibits Tumor Growth, Epithelial-Mesenchymal Transition, Metastases, and Improves Antitumor Immunity in Preclinical Models of Lung Cancer

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Qianwen ZhangKer Yu

Abstract

We aimed to investigate efficacy and mechanism of MTI-31 (LXI-15029), a novel mTORC1/mTORC2 inhibitor currently in human trial (NCT03125746), in non-small cell lung cancer (NSCLC) models of multiple driver mutations and tyrosine kinase inhibitor (TKI)-resistance. Gene depletion, inhibitor treatment, immunological, flow cytometry, cellular, and animal studies were performed to determine in vitro and in vivo efficacy in NSCLC models of driver mutations and elucidate roles by mTOR complexes in regulating migration, epithelial-mesenchymal transition (EMT), metastasis, intracranial tumor growth, and immune-escape. MTI-31 potently inhibited cell proliferation (IC50 <1 μmol/L) and in vivo tumor growth in multiple NSCLC models of EGFR/T790M, EML4-ALK, c-Met, or KRAS (MED <10 mg/kg). In EGFR-mutant and/or EML4-ALK-driven NSCLC, MTI-31 or disruption of mTORC2 reduced cell migration, hematogenous metastasis to the lung, and abrogated morphological and functional traits of EMT. Disruption of mTORC2 inhibited EGFR/T790M-positive tumor growth in mouse brain and prolonged animal survival correlating a diminished tumor angiogenesis and recruitment of IBA1+ microglia/macrophages in tumor microenvironment. MTI-31 also suppressed programmed death...Continue Reading

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Citations

Sep 15, 2020·Frontiers in Oncology·Ying CongKer Yu
May 16, 2020·Journal of Immunology Research·Pengyu JingZhongping Gu
Nov 8, 2020·Cell Death & Disease·Qian GouYongzhong Hou
Oct 13, 2019·Cancer Letters·Yuanyuan Jiang, Hanxiang Zhan
Feb 5, 2021·Frontiers in Oncology·Yalin KangXianglin Yuan
Feb 15, 2020·Pathology, Research and Practice·Zhu LinglingZhou Qinghua
May 27, 2021·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Chenhe YiJinhong Chen

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