Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, China.
Clin Cancer Res. 2019 Jun 15;25(12):3630-3642. doi: 10.1158/1078-0432.CCR-18-2548. Epub 2019 Feb 22.
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 and 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 (IC <1 μmol/L) and 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 coculture system.
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 patients with lung cancer.
我们旨在研究 LXI-15029（新型 mTORC1/mTORC2 抑制剂，目前正在进行人体试验[NCT03125746]）在多种驱动基因突变和酪氨酸激酶抑制剂（TKI）耐药的非小细胞肺癌（NSCLC）模型中的疗效和机制。
通过基因缺失、抑制剂处理、免疫、流式细胞术、细胞和动物研究，确定在驱动基因突变的 NSCLC 模型中 和 的疗效，并阐明 mTOR 复合物在调节迁移、上皮-间充质转化（EMT）、转移、颅内肿瘤生长和免疫逃逸中的作用。
MTI-31 能有效抑制 EGFR/T790M、EML4-ALK、c-Met 或 KRAS 多种 NSCLC 模型中的细胞增殖（IC <1 μmol/L）和 肿瘤生长（MED <10 mg/kg）。在 EGFR 突变和/或 EML4-ALK 驱动的 NSCLC 中，MTI-31 或 mTORC2 的破坏降低了细胞迁移、血液向肺转移的能力，并消除了 EMT 的形态和功能特征。mTORC2 的破坏抑制了 EGFR/T790M 阳性肿瘤在小鼠大脑中的生长，并延长了动物的存活时间，这与肿瘤微环境中肿瘤血管生成和 IBA1+小胶质细胞/巨噬细胞的募集减少有关。MTI-31 还抑制了 EGFR 和 ALK 驱动的 NSCLC 中的程序性死亡配体 1（PD-L1），部分通过 mTORC2/AKT/GSK3β 依赖性蛋白酶体降解介导。mTOR 蛋白的缺失或 mTOR 复合物的破坏在肿瘤 T 细胞共培养系统中，显著下调了 Jurkat T 和原代人 T 细胞中的 PD-L1，并减轻了细胞凋亡。
我们的结果强调了 mTOR 作为 EGFR/ALK 突变和 TKI 耐药 NSCLC 细胞中肿瘤生长、转移和免疫逃逸的多方面调节剂。新发现的由雷帕霉素抗性 mTORC2 介导的机制为研究 mTORC1/mTORC2 抑制剂在肺癌患者中的应用提供了依据。
