MEK or ERK inhibition effectively abrogates emergence of acquired osimertinib resistance in the treatment of epidermal growth factor receptor-mutant lung cancers
MEK or ERK inhibition effectively abrogates emergence of acquired osimertinib resistance in the treatment of epidermal growth factor receptor-mutant lung cancers
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DOI：
10.1002/cncr.32996
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发表时间：
2020-06-04
期刊：
影响因子：
6.2
通讯作者：
Sun, Shi-Yong
中科院分区：
文献类型：
--
作者：
Gu, Jiajia;Yao, Weilong;Sun, Shi-Yong
背景 大多数携带表皮生长因子受体 (EGFR) 激活突变的非小细胞肺癌 (NSCLC) 患者对第三代突变选择性 EGFR 抑制剂奥希替尼 (AZD9291) 反应良好。目前的研究重点是确定靶向 MEK/ERK 信号传导是否可以预防或延缓奥希替尼获得性耐药的发展。方法通过测量细胞数量的变化来确定药物对细胞存活的影响。通过流式细胞术检测膜联蛋白 V 阳性细胞并通过蛋白质印迹法检测蛋白质裂解来评估细胞凋亡。通过蛋白质印迹检测细胞中蛋白质的变化。通过体外集落形成和体内裸鼠异种移植来评估药物延迟奥希替尼耐药出现的作用。结果奥希替尼与 MEK 或 ERK 抑制剂联合使用，可协同降低细胞存活率，并增强 EGFR 突变型 NSCLC 细胞的凋亡诱导，但对 EGFR 野生型 NSCLC 细胞无影响。这些组合在杀死对奥希替尼具有原发性内在耐药性的细胞克隆方面也非常有效。 MEK/ERK信号传导的连续和间歇性药理抑制在体外和体内均延迟了奥希替尼耐药的出现。结论这些结果提供了强有力的临床前证据，支持将靶向MEK/ERK信号作为延迟或预防临床上对奥希替尼获得性耐药的策略，以提高奥希替尼的长期治疗效果。从临床角度来看，这些数据支持对 EGFR 突变 NSCLC 患者中奥希替尼联合 MEK 或 ERK 抑制剂的间歇治疗方案进行评估。
Background The majority of patients with non-small cell lung cancer (NSCLC) harboring activating epidermal growth factor receptor (EGFR) mutations respond well to osimertinib (AZD9291), a third-generation, mutation-selective EGFR inhibitor. The current study focuses on determining whether targeting MEK/ERK signaling prevents or delays the development of acquired resistance to osimertinib.Methods Drug effects on cell survival were determined by measuring cell number alterations. Apoptosis was assessed with flow cytometry for the detection of annexin V-positive cells and with Western blotting for protein cleavage. Alterations of proteins in cells were detected with Western blotting. Drug effects on delaying the emergence of osimertinib resistance were evaluated with colony formation in vitro and xenografts in nude mice in vivo.Results Osimertinib combined with an MEK or ERK inhibitor synergistically decreased cell survival with enhanced induction of apoptosis in EGFR-mutant NSCLC cells but not in EGFR wild-type NSCLC cells. These combinations were also very effective in killing cell clones with primary intrinsic resistance to osimertinib. Continuous and intermittent pharmacologic inhibition of MEK/ERK signaling delayed the emergence of osimertinib resistance both in vitro and in vivo.Conclusions These results provide strong preclinical evidence in support of targeting MEK/ERK signaling as a strategy for delaying or preventing acquired resistance to osimertinib in the clinic to improve the long-term therapeutic efficacy of osimertinib. From a clinical standpoint, the data support the evaluation of an intermittent treatment schedule of osimertinib in combination with an MEK or ERK inhibitor in patients with EGFR-mutated NSCLC.