Wu D-W, Chen C-Y, Chu C-L, Lee H
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan, ROC.
Cancer Center, China Medical University Hospital, Taichung, Taiwan, ROC.
Oncogene. 2016 Feb 4;35(5):621-30. doi: 10.1038/onc.2015.120. Epub 2015 Apr 27.
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.
酪氨酸激酶抑制剂（TKIs）已被证明对表皮生长因子受体（EGFR）突变的非小细胞肺癌具有显著的临床益处。几乎所有接受TKI靶向治疗的患者都会出现TKI耐药，导致总体生存获益有限。因此，建立早期预测的生物标志物并探索原发性TKI耐药的机制对于提高非小细胞肺癌患者的治疗效果至关重要。在本研究中，我们提供证据表明桩蛋白（PXN）过表达可能赋予EGFR突变肺癌细胞TKI耐药性。从机制上讲，PXN介导的细胞外信号调节激酶（ERK）激活通过降低细胞死亡的Bcl2相互作用介质（BIM）和增加Mcl-1表达导致TKI耐药，这是由于通过在丝氨酸69处磷酸化BIM和在苏氨酸163处磷酸化Mcl-1来调节它们的蛋白质稳定性。通过在裸鼠中观察异种移植肿瘤进一步证实了细胞模型中的机制作用，表明PXN介导的TKI耐药被ERK抑制剂（AZD6244）和Bcl-2家族抑制剂（obatoclax）克服，但AZD6244克服的TKI耐药比obatoclax更有效。因此，我们认为PXN表达可能有助于预测原发性TKI耐药，并且将TKI与ERK抑制剂联合使用可能对肿瘤表现出高PXN表达的EGFR突变非小细胞肺癌患者具有临床益处。
