ERK1/2 blockade prevents epithelial-mesenchymal transition in lung cancer cells and promotes their sensitivity to EGFR inhibition.
ERK1/2 blockade prevents epithelial-mesenchymal transition in lung cancer cells and promotes their sensitivity to EGFR inhibition.
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DOI：
10.1158/0008-5472.can-12-4721
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发表时间：
2014-01-01
期刊：
影响因子：
11.2
通讯作者：
Lazzara MJ
中科院分区：
文献类型：
--
作者：
Buonato JM;Lazzara MJ
克服新生和获得性耐药的细胞机制仍然是许多癌症（包括非小细胞肺癌（NSCLC））临床管理的核心挑战。虽然许多工作已经将癌细胞中的上皮-间充质转化（EMT）与耐药性的出现联系起来，但尚不清楚在哪里可以存在易于处理的途径来逆转或抑制EMT作为药物致敏的策略。在这里，我们证明了ERK 1/2（MAPK 3/1）信号传导在指导NSCLC细胞的间充质特性中起着关键作用，并且阻断ERK信号传导足以提高对EGFR抑制剂的治疗反应。MEK 1/2（MAPKK 1/2）抑制促进NSCLC细胞的上皮表型，阻止外源性TGFβ诱导EMT。此外，在对EGFR抑制剂吉非替尼表现出新生或获得性耐药性的细胞中，MEK抑制增强了对吉非替尼的敏感性并减缓了细胞迁移。然而，只有在MEK被抑制足以触发EMT标志物表达变化的时间段内，才会发生这些效应。与这些发现一致，EMT表型和标志物的变化也由突变KRAS以MEK依赖性方式的表达诱导。我们的研究结果表明，长期暴露于MEK或ERK抑制剂不仅可以抑制EMT，而且可以克服NSCLC对EGFR靶向治疗的初始或获得性耐药。
Overcoming cellular mechanisms of de novo and acquired resistance to drug therapy remains a central challenge in the clinical management of many cancers, including non-small cell lung cancer (NSCLC). While much work has linked the epithelial-mesenchymal transition (EMT) in cancer cells to the emergence of drug resistance, it is less clear where tractable routes may exist to reverse or inhibit EMT as a strategy for drug sensitization. Here, we demonstrate that ERK1/2 (MAPK3/1) signaling plays a key role in directing the mesenchymal character of NSCLC cells, and that blocking ERK signaling is sufficient to heighten therapeutic responses to EGFR inhibitors. MEK1/2 (MAPKK1/2) inhibition promoted an epithelial phenotype in NSCLC cells, preventing induction of EMT by exogenous TGFβ. Moreover, in cells exhibiting de novo or acquired resistance to the EGFR inhibitor gefitinib, MEK inhibition enhanced sensitivity to gefitinib and slowed cell migration. These effects only occurred, however, if MEK was inhibited for a period sufficient to trigger changes in EMT marker expression. Consistent with these findings, changes in EMT phenotypes and markers were also induced by expression of mutant KRAS in a MEK-dependent manner. Our results suggest that prolonged exposure to MEK or ERK inhibitors may not only restrain EMT but overcome naïve or acquired resistance of NSCLC to EGFR-targeted therapy in the clinic.