https://scholars.lib.ntu.edu.tw/handle/123456789/638329
標題: | EGFR-T790M Mutation-Derived Interactome Rerouted EGFR Translocation Contributing to Gefitinib Resistance in Non-Small Cell Lung Cancer | 作者: | Wu, Pei-Shan MIAO-HSIA LIN Hsiao, Jye-Chian Lin, Pei-Yi SZU-HUA PAN Chen, Yu-Ju |
關鍵字: | T790M mutation; TKI-resistance; autophagy; epidermal growth factor receptor; non-small cell lung cancer; protein-protein interaction; tyrosine kinase inhibitor | 公開日期: | 九月-2023 | 出版社: | ELSEVIER | 卷: | 22 | 期: | 9 | 來源出版物: | Molecular and Cellular Proteomics | 摘要: | Secondary mutation, T790M, conferring tyrosine kinase inhibitors (TKIs) resistance beyond oncogenic epidermal growth factor receptor (EGFR) mutations presents a challenging unmet need. Although TKI-resistant mechanisms are intensively investigated, the underlying responses of cancer cells adapting drug perturbation are largely unknown. To illuminate the molecular basis linking acquired mutation to TKI resistance, affinity purification coupled mass spectrometry was adopted to dissect EGFR interactome in TKI-sensitive and TKI-resistant non-small cell lung cancer cells. The analysis revealed TKI-resistant EGFR-mutant interactome allocated in diverse subcellular distribution and enriched in endocytic trafficking, in which gefitinib intervention activated autophagy-mediated EGFR degradation and thus autophagy inhibition elevated gefitinib susceptibility. Alternatively, gefitinib prompted TKI-sensitive EGFR translocating toward cell periphery through Rab7 ubiquitination which may favor efficacy to TKIs suppression. This study revealed that T790M mutation rewired EGFR interactome that guided EGFR to autophagy-mediated degradation to escape treatment, suggesting that combination therapy with TKI and autophagy inhibitor may overcome acquired resistance in non-small cell lung cancer. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/638329 | ISSN: | 15359476 | DOI: | 10.1016/j.mcpro.2023.100624 |
顯示於: | 微生物學科所 |
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