Lawrence J. Ellison Institute for Transformative Medicine of USC, University of Southern California, Los Angeles, CA, USA.
Lawrence J. Ellison Institute for Transformative Medicine of USC, University of Southern California, Los Angeles, CA, USA.
Cancer Lett. 2018 Oct 10;434:152-159. doi: 10.1016/j.canlet.2018.07.025. Epub 2018 Jul 21.
Non-small cell lung cancer (NSCLC) patients with activating EGFR mutations are often successfully treated with EGFR tyrosine kinase inhibitor (TKI) such as erlotinib; however, treatment resistance inevitably occurs. Given tumor metabolism of glucose and therapeutic response are intimately linked, we explored the metabolic differences between isogenic erlotinib-sensitive and -resistant NSCLC cell lines. We discovered that the growth of erlotinib-resistant cells is more sensitive to glucose deprivation. Seahorse metabolic assay revealed erlotinib-resistant cells have lower spare respiratory capacity (SRC), an indicator of metabolic flexibility, compared to erlotinib-sensitive cells. Additionally, we found downstream components of mTORC2 signaling to be phosphorylated in erlotinib-resistant cells. Knockdown of an mTORC2 component, Rictor, enhanced the SRC and rescued the growth rate of erlotinib-resistant cells during glucose deprivation. Among NSCLCs with activating EGFR mutations, gene sets involved in glucose metabolism were enriched in patients with high expression of p-NDGR1, a readout of mTORC2 activity. Furthermore, overall survival was negatively correlated with p-NDRG1. Our work uncovers a link between mTORC2 and metabolic reprogramming in EGFR TKI-resistant cells and highlights the significance of mTORC2 in the progression of EGFR-mutated NSCLC.
非小细胞肺癌 (NSCLC) 患者中存在激活的 EGFR 突变时，通常可以通过 EGFR 酪氨酸激酶抑制剂 (TKI) 如厄洛替尼成功治疗；然而，治疗耐药性不可避免会发生。鉴于肿瘤代谢与治疗反应密切相关，我们探索了同源性厄洛替尼敏感和耐药 NSCLC 细胞系之间的代谢差异。我们发现，厄洛替尼耐药细胞的生长对葡萄糖剥夺更为敏感。 Seahorse 代谢测定显示，与厄洛替尼敏感细胞相比，厄洛替尼耐药细胞的备用呼吸能力 (SRC) 较低，这是代谢灵活性的指标。此外，我们发现 mTORC2 信号下游成分在厄洛替尼耐药细胞中被磷酸化。敲低 mTORC2 成分 Rictor 可增强 SRC 并在葡萄糖剥夺时挽救厄洛替尼耐药细胞的生长速率。在具有激活的 EGFR 突变的 NSCLC 中，参与葡萄糖代谢的基因集在 mTORC2 活性的读码器 p-NDGR1 高表达的患者中富集。此外，总生存期与 p-NDRG1 呈负相关。我们的工作揭示了 mTORC2 与 EGFR TKI 耐药细胞中代谢重编程之间的联系，并强调了 mTORC2 在 EGFR 突变型 NSCLC 进展中的重要性。
