Paxillin confers resistance to tyrosine kinase inhibitors in EGFR-mutant lung cancers via modulating BIM and Mcl-1 protein stability

D. W. Wu, C. Y. Chen, C. L. Chu, H. Lee

研究成果: 雜誌貢獻文章

24 引文 斯高帕斯(Scopus)

摘要

Tyrosine kinase inhibitors (TKIs) have been documented to have substantial clinical benefits to non-small cell lung cancer with epidermal growth factor receptor (EGFR) mutation. TKI resistance occurs in nearly all patients who receive TKI-targeting therapy, resulting in a modest overall survival benefit. Therefore, establishing a biomarker for early prediction and exploring the mechanism of primary TKI resistance is essential for improving the therapeutic efficacy in non-small cell lung cancer patients. In this study, we provide evidence indicating that paxillin (PXN) overexpression may confer TKI resistance in EGFR-mutant lung cancer cells. Mechanistically, PXN-mediated extracellular signal-regulated kinases (ERK) activation is responsible for TKI resistance via decreased Bcl2-interacting mediator of cell death (BIM) and increased Mcl-1 expression due to modulating their protein stabilities by phosphorylation of BIM at serine 69 and Mcl-1 at threonine 163. The mechanistic action in the cell model was further confirmed by the observation of xenograft tumors in nude mice, revealing that the PXN-mediated TKI resistance was conquered by ERK inhibitor (AZD6244) and Bcl-2 family inhibitor (obatoclax), but the TKI resistance overcome by AZD6244 is more effective than that of obatoclax. Therefore, we suggest that PXN expression may be useful in predicting primary TKI resistance, and combining TKI with ERK inhibitors may clinically benefit EGFR-mutant non-small cell lung cancer patients whose tumors exhibit high PXN expression.
原文英語
頁(從 - 到)621-630
頁數10
期刊Oncogene
35
發行號5
DOIs
出版狀態已發佈 - 二月 4 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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