First-generation EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib have significant activity in NSCLC patients with activating EGFR mutations. However, EGFR-TKI resistance inevitably occurs after approximately 12 months of treatment. Acquired mechanisms of resistance, other than secondary mutations in EGFR (T790 M) which account for 50-60%, are less well understood. Here, we identified lncRNA H19 as a significantly downregulated lncRNA in vitro models and clinical specimens with acquired EGFR-TKI resistance, H19 knockdown or overexpression conferred resistance or sensitivity, respectively, both in vitro and in vivo models. H19 downregulation contributed to erlotinib resistance through interaction and upregulation of PKM2, which enhanced the phosphorylation of AKT. AKT inhibitors restored the sensitivity of erlotinib-resistant cells to erlotinib. In EGFR-mutant patients treated with EGFR-TKIs, low H19 levels were associated with a shorter progression-free survival (PFS) (P = 0.021). These findings revealed a novel mechanism of low-level H19 in the regulation of erlotinib resistance in EGFR-mutant lung cancers. Combination of AKT inhibitors and EGFR-TKIs could be a rational therapeutic approach for some subgroups of EGFR-mutant lung cancer patients.

中文翻译：

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在 EGFR 突变型肺癌中，LncRNA H19 下调通过上调 PKM2 和 AKT 磷酸化而赋予厄洛替尼耐药性。


第一代 EGFR 酪氨酸激酶抑制剂 (TKI)，例如厄洛替尼，对具有激活 EGFR 突变的 NSCLC 患者具有显着的活性。然而，治疗约 12 个月后，不可避免地会出现 EGFR-TKI 耐药。除了占 50-60% 的 EGFR 二次突变 (T790 M) 之外，获得性耐药机制尚不清楚。在这里，我们将lncRNA H19确定为体外模型和具有获得性EGFR-TKI耐药性的临床标本中显着下调的lncRNA，在体外和体内模型中，H19敲低或过表达分别赋予耐药性或敏感性。 H19 下调通过 PKM2 的相互作用和上调导致厄洛替尼耐药，从而增强 AKT 的磷酸化。 AKT 抑制剂恢复了厄洛替尼耐药细胞对厄洛替尼的敏感性。在接受 EGFR-TKI 治疗的 EGFR 突变患者中，低 H19 水平与较短的无进展生存期 (PFS) 相关 (P = 0.021)。这些发现揭示了低水平 H19 在调节 EGFR 突变型肺癌埃罗替尼耐药性中的新机制。 AKT 抑制剂和 EGFR-TKI 的组合可能是针对 EGFR 突变肺癌患者的某些亚组的合理治疗方法。