BACKGROUND Osimertinib (AZD9291), a third-generation, mutation-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI), is an approved drug for patients who have non-small cell lung cancer (NSCLC) with activating EGFR mutations or those harboring a resistant T790M mutation. Unfortunately, all patients eventually relapse and develop resistance to osimertinib. The current study addressed whether ERK inhibition exerts effects similar to those produced by MEK inhibition in overcoming acquired resistance to osimertinib. METHODS Drug effects on cell and tumor growth were assessed by measuring cell number alterations and colony formation in vitro and with xenografts in nude mice in vivo. Apoptosis was assessed with annexin V/flow cytometry and protein cleavage. Protein alterations in cells were detected with Western blot analysis. Gene overexpression and knockout were achieved with lentiviral infection and CRISPR/Cas9, respectively. RESULTS The combination of osimertinib with an ERK inhibitor synergistically decreased the survival of osimertinib-resistant cell lines with enhanced induction of apoptosis and effectively inhibited the growth of osimertinib-resistant xenografts in nude mice. Moreover, the combination of an MEK or ERK inhibitor with a first-generation (eg, erlotinib) or second-generation (eg, afatinib) EGFR-TKI also very effectively inhibited the growth of osimertinib-resistant cells in vitro and of tumors in vivo, although these cell lines were cross-resistant to first-generation or second-generation EGFR-TKIs. CONCLUSIONS The current findings emphasize the importance of targeting MEK/ERK signaling in maintaining the long-term benefit of osimertinib through overcoming acquired resistance to osimertinib, warranting further investigation of this therapeutic strategy to improve the therapeutic efficacy of osimertinib in the clinic.

中文翻译：

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ERK抑制有效克服了表皮生长因子受体突变非小细胞肺癌细胞对奥希替尼的获得性耐药。

背景奥希替尼 (AZD9291) 是一种第三代突变选择性表皮生长因子受体 (EGFR) 酪氨酸激酶抑制剂 (EGFR-TKI)，是一种获批用于具有激活 EGFR 的非小细胞肺癌 (NSCLC) 患者的药物突变或具有抗性 T790M 突变的那些。不幸的是，所有患者最终都会复发并对奥希替尼产生耐药性。目前的研究探讨了 ERK 抑制在克服对奥希替尼的获得性耐药方面是否发挥类似于 MEK 抑制所产生的效果。方法 药物对细胞和肿瘤生长的影响通过在体外测量细胞数量变化和集落形成以及在体内裸鼠的异种移植物来评估。用膜联蛋白 V/流式细胞术和蛋白质切割评估细胞凋亡。用蛋白质印迹分析检测细胞中的蛋白质变化。分别用慢病毒感染和 CRISPR/Cas9 实现基因过表达和敲除。结果 奥希替尼与ERK抑制剂的组合协同降低了奥希替尼耐药细胞系的存活率，增强了细胞凋亡的诱导作用，并有效抑制了裸鼠体内奥希替尼耐药异种移植物的生长。此外，MEK 或 ERK 抑制剂与第一代（例如，厄洛替尼）或第二代（例如，阿法替尼）EGFR-TKI 的组合也非常有效地抑制体外奥希替尼耐药细胞和体内肿瘤的生长，尽管这些细胞系对第一代或第二代 EGFR-TKI 具有交叉耐药性。