A novel mTORC1/2 inhibitor (MTI-31) inhibits tumor growth, epithelial-mesenchymal transition, metastases and improves cancer immunity in preclinical lung cancer models

Purpose: 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. Experimental design: 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. Results: MTI-31 potently inhibited cell proliferation (IC₅₀ <1 mmol/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 ligand 1 (PD-L1) in EGFR- and ALK-driven NSCLC, mediated in part by mTORC2/AKT/GSK3β-dependent proteasomal degradation. Depletion of mTOR protein or disruption of mTOR-complexes profoundly downregulated PD-L1 and alleviated apoptosis in Jurkat T and primary human T cells in a tumor-T cell co-culture system. Conclusions: Our results highlight mTOR as a multifaceted regulator of tumor growth, metastasis and immune-escape in EGFR/ALK-mutant and TKI-resistant NSCLC cells. The newly characterized mechanisms mediated by the rapamycin-resistant mTORC2 warrant clinical investigation of mTORC1/mTORC2 inhibitors in lung cancer patients.

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