Inhibition of oxidative phosphorylation suppresses the development of osimertinib resistance in a preclinical model of EGFR-driven lung adenocarcinoma.
Inhibition of oxidative phosphorylation suppresses the development of osimertinib resistance in a preclinical model of EGFR-driven lung adenocarcinoma.
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DOI：
10.18632/oncotarget.13388
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发表时间：
2016-12-27
期刊：
影响因子：
--
通讯作者：
Cross D
中科院分区：
文献类型：
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作者：
Martin MJ;Eberlein C;Taylor M;Ashton S;Robinson D;Cross D
代谢可塑性是癌症的一个新的标志，并且在转化细胞中经常观察到糖酵解增加。靶向驱动致癌基因的小分子抑制剂可以潜在地抑制糖酵解途径。奥希替尼（AZD 9291）是一种新型EGFR酪氨酸激酶抑制剂（TKI），对致敏（EGFRm）和T790 M耐药突变具有强效和选择性。临床研究表明，奥希替尼对EGFR-TKI治疗后进展的EGFRm/T790 M晚期NSCLC患者有效。然而，靶向治疗的经验表明，可能会出现获得性耐药性。因此，需要表征耐药机制并设计预防、延迟或克服奥希替尼耐药的方法。我们在这里发现，奥希替尼抑制亲本EGFR突变型肺腺癌细胞系的糖酵解，但在奥希替尼耐药细胞系中没有。重要的是，我们发现奥希替尼治疗诱导了对线粒体氧化磷酸化（OxPhos）的严格依赖，因为OxPhos抑制剂显著延迟了奥希替尼敏感细胞系中奥希替尼耐药性的长期发展。因此，促进较少糖酵解表型的生长条件赋予一定程度的奥希替尼抗性。我们的数据支持一种模型，其中奥希替尼和OxPhos抑制剂的组合可以延迟或预防奥希替尼初始肿瘤细胞的耐药性，并且代表了一种新的策略，值得进一步的临床前研究。
Metabolic plasticity is an emerging hallmark of cancer, and increased glycolysis is often observed in transformed cells. Small molecule inhibitors that target driver oncogenes can potentially inhibit the glycolytic pathway. Osimertinib (AZD9291) is a novel EGFR tyrosine kinase inhibitor (TKI) that is potent and selective for sensitising (EGFRm) and T790M resistance mutations. Clinical studies have shown osimertinib to be efficacious in patients with EGFRm/ T790M advanced NSCLC who have progressed after EGFR-TKI treatment. However experience with targeted therapies suggests that acquired resistance may emerge. Thus there is a need to characterize resistance mechanisms and to devise ways to prevent, delay or overcome osimertinib resistance. We show here that osimertinib suppresses glycolysis in parental EGFR-mutant lung adenocarcinoma lines, but has not in osimertinib-resistant cell lines. Critically, we show osimertinib treatment induces a strict dependence on mitochondrial oxidative phosphorylation (OxPhos), as OxPhos inhibitors significantly delay the long-term development of osimertinib resistance in osimertinib-sensitive lines. Accordingly, growth conditions which promote a less glycolytic phenotype confer a degree of osimertinib resistance. Our data support a model in which the combination of osimertinib and OxPhos inhibitors can delay or prevent resistance in osimertinib-naïve tumour cells, and represents a novel strategy that warrants further pre-clinical investigation.