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Epithelial-mesenchymal transition (EMT) beyond EGFR mutations per se is a common mechanism for acquired resistance to EGFR TKI

Oncogene volume 38, pages 455–468 (2019)Cite this article

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Abstract

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is a major advance in treating NSCLC with EGFR-activating mutations. However, acquired resistance, due partially to secondary mutations limits their use. Here we report that NSCLC cells with acquired resistance to gefitinib or osimertinib (AZD9291) exhibit EMT features, with a decrease in E-cadherin, and increases in vimentin and stemness, without possessing any EGFR secondary mutations. Knockdown of E-cadherin in parental cells increased gefitinib resistance and stemness, while knockdown of vimentin in resistant cells resulted in opposite effects. Src activation and Hakai upregulation were found in gefitinib-resistant cells. Knockdown of Hakai elevated E-cadherin expression, attenuated stemness, and resensitized the cells to gefitinib. Clinical cancer specimens with acquired gefitinib resistance also showed a decrease in E-cadherin and an increase in Hakai expression. The dual HDAC and HMGR inhibitor JMF3086 inhibited the Src/Hakai and Hakai/E-cadherin interaction to reverse E-cadherin expression, and attenuated vimentin and stemness to restore gefitinib sensitivity. The EMT features of AZD9291-resistant H1975 cells were related to the upregulation of Zeb1. Both gefitinib and AZD9291 sensitivity was restored by JMF3086 through reversing EMT. Our study not only revealed a common mechanism of EMT in both gefitinib and AZD9291 resistance beyond EGFR mutations per se, but also provides a new strategy to overcome it.

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Author notes

  1. These authors contributed equally: Chien-Hui Weng, Li-Yu Chen, Yu-Chin Lin.

Authors and Affiliations

  1. Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan

    Chien-Hui Weng, Li-Yu Chen, Yu-Chin Lin, Yun-Chieh Lin, Ruo-Yu Tseng, An-Chieh Chiu, Yu-Hsuan Yeh, Chi Liu, Yi-Ting Lin & Ching-Chow Chen

  2. Department of Internal Medicine, Mennonite Christian Hospital, Hualien, Taiwan

    Yu-Chin Lin

  3. Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

    Jin-Yuan Shih

  4. Department of Chemistry, National Taiwan University, Taipei, Taiwan

    Jim-Min Fang

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  1. Chien-Hui Weng
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Correspondence to Ching-Chow Chen.

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Acknowledgements

This work was supported by grants from the Ministry of Science and Technology (MOST-106-2320-B002-003), Excellent Translational Medicine Research Projects of National Taiwan University, College of Medicine and National Taiwan University Hospital (106R39012), and the National Health Research Institute of Taiwan (NHRI-EX107-10707BI). We thank the technical assistance of the First Core Labs in the National Taiwan University College of Medicine.

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Weng, CH., Chen, LY., Lin, YC. et al. Epithelial-mesenchymal transition (EMT) beyond EGFR mutations per se is a common mechanism for acquired resistance to EGFR TKI. Oncogene 38, 455–468 (2019). https://doi.org/10.1038/s41388-018-0454-2

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