Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon, Korea.
Cancer Res Treat. 2023 Jul;55(3):851-864. doi: 10.4143/crt.2022.1527. Epub 2023 Mar 20.
The mammalian target of rapamycin complex 1 (mTORC1) regulates cell growth and proliferation by growth factor coordination and amino acid availability. Leucyl-tRNA synthetase 1 (LARS1) senses the intracellular leucine concentration and mediates amino acid-induced activation of mTORC1. Thus, LARS1 inhibition could be useful in cancer treatment. However, the fact that mTORC1 can be stimulated by various growth factors and amino acids suggests that LARS1 inhibition alone has limitations in inhibiting cell growth and proliferation. We investigated the combined effects of BC-LI-0186, a LARS1 inhibitor, and trametinib, an MEK inhibitor, on non-small cell lung cancer (NSCLC).
Protein expression and phosphorylation were observed by immunoblotting, and genes differentially expressed between BC-LI-0186-sensitive and -resistant cells were identified by RNA sequencing. The combined effect of the two drugs was inferred from the combination index values and a xenograft model.
LARS1 expression was positively correlated with mTORC1 in NSCLC cell lines. BC-LI-0186 treatment of A549 and H460 cells maintained in media supplemented with fetal bovine serum revealed paradoxical phosphorylation of S6 and activation of mitogen- activated protein kinase (MAPK) signaling. Compared with BC-LI-0186-sensitive cells, -resistant cells showed enrichment of the MAPK gene set. The combination of trametinib and BC-LI-0186 inhibited the phosphorylation of S6, MEK, and extracellular signal-regulated kinase and their synergistic effects were confirmed in a mouse xenograft model.
The combination of BC-LI-0186 and trametinib inhibited the non-canonical mTORC1-activating function of LARS1. Our study demonstrated a new therapeutic approach for NSCLC without targetable driver mutations.
哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）通过生长因子协调和氨基酸可用性来调节细胞生长和增殖。亮氨酰-tRNA 合成酶 1（LARS1）感知细胞内亮氨酸浓度，并介导氨基酸诱导的 mTORC1 激活。因此，LARS1 抑制可能对癌症治疗有用。然而，mTORC1 可以被各种生长因子和氨基酸刺激这一事实表明，仅 LARS1 抑制在抑制细胞生长和增殖方面存在局限性。我们研究了 LARS1 抑制剂 BC-LI-0186 和 MEK 抑制剂 trametinib 对非小细胞肺癌（NSCLC）的联合作用。
通过免疫印迹观察蛋白质表达和磷酸化，通过 RNA 测序鉴定 LARS1 敏感和耐药细胞之间差异表达的基因。通过组合指数值和异种移植模型推断两种药物的联合效应。
LARS1 表达与 NSCLC 细胞系中的 mTORC1 呈正相关。在含有胎牛血清的培养基中维持的 A549 和 H460 细胞中用 BC-LI-0186 处理，揭示了 S6 的矛盾性磷酸化和丝裂原激活蛋白激酶（MAPK）信号的激活。与 LARS1 敏感细胞相比，耐药细胞中 MAPK 基因集富集。trametini 和 BC-LI-0186 的联合抑制了 S6、MEK 和细胞外信号调节激酶的磷酸化，并且在小鼠异种移植模型中证实了它们的协同作用。
BC-LI-0186 和 trametinib 的联合抑制了 LARS1 的非典型 mTORC1 激活功能。我们的研究为没有可靶向驱动突变的 NSCLC 提供了一种新的治疗方法。
