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

Oncogene volume 35, pages 621–630 (2016)Cite this article

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Abstract

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.

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Acknowledgements

This work was jointly supported by grants from the National Health Research Institute (NHRI-EX103-10328BI) and the National Science Council (NSC100-2314-B-038-043-MY3) of Taiwan, ROC.

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Authors and Affiliations

  1. Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan, ROC

    D-W Wu & H Lee

  2. Cancer Center, China Medical University Hospital, Taichung, Taiwan, ROC

    C-Y Chen & C-L Chu

  3. Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan, ROC

    C-Y Chen

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  1. D-W Wu
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  4. H Lee
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Correspondence to H Lee.

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Wu, DW., Chen, CY., Chu, CL. et al. Paxillin confers resistance to tyrosine kinase inhibitors in EGFR-mutant lung cancers via modulating BIM and Mcl-1 protein stability. Oncogene 35, 621–630 (2016). https://doi.org/10.1038/onc.2015.120

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