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EGFR-T790M Mutation-Derived Interactome Rerouted EGFR Translocation Contributing to Gefitinib Resistance in Non-Small Cell Lung Cancer.
- Source :
-
Molecular & cellular proteomics : MCP [Mol Cell Proteomics] 2023 Sep; Vol. 22 (9), pp. 100624. Date of Electronic Publication: 2023 Jul 24. - Publication Year :
- 2023
-
Abstract
- 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.<br /> (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Humans
Gefitinib pharmacology
ErbB Receptors genetics
Mutation genetics
Protein Kinase Inhibitors pharmacology
Protein Kinase Inhibitors therapeutic use
Drug Resistance, Neoplasm genetics
Cell Line, Tumor
Carcinoma, Non-Small-Cell Lung drug therapy
Carcinoma, Non-Small-Cell Lung genetics
Carcinoma, Non-Small-Cell Lung metabolism
Lung Neoplasms drug therapy
Lung Neoplasms genetics
Lung Neoplasms metabolism
Antineoplastic Agents pharmacology
Antineoplastic Agents therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1535-9484
- Volume :
- 22
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Molecular & cellular proteomics : MCP
- Publication Type :
- Academic Journal
- Accession number :
- 37495186
- Full Text :
- https://doi.org/10.1016/j.mcpro.2023.100624