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

• Published in: Oncogene Vol. 35; no. 5; pp. 621 - 630
• Main Authors: Wu, D-W, Chen, C-Y, Chu, C-L, Lee, H
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.02.2016; Nature Publishing Group
• Subjects: 38/109; 631/67/1059/2326; 82/80; Animals; Apoptosis; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Bcl-2 protein; Bcl-2-Like Protein 11; BIM protein; Biomarkers; Care and treatment; Carrier proteins; Cell Biology; Cell death; Cell Line, Tumor; Development and progression; Drug resistance; Drug Resistance, Neoplasm; Enzyme inhibitors; Epidermal growth factor; Epidermal growth factor receptors; Extracellular signal-regulated kinase; Female; Gene expression; Gene mutations; Genetic aspects; Health aspects; Human Genetics; Humans; Internal Medicine; Kinases; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Mcl-1 protein; Medical prognosis; Medicine; Medicine & Public Health; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred BALB C; Mice, Nude; Mutants; Myeloid Cell Leukemia Sequence 1 Protein - genetics; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; Non-small cell lung carcinoma; Oncology; original-article; Patient outcomes; Patients; Paxillin; Paxillin - genetics; Paxillin - metabolism; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Protein Stability; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Random Allocation; Receptor, Epidermal Growth Factor - genetics; Small cell lung carcinoma; Threonine; Tumors; Tyrosine kinase inhibitors; Xenograft Model Antitumor Assays; Xenografts; Taiwan
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2015.120

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.