Targeting MET endocytosis or degradation to overcome HGF-induced gefitinib resistance in EGFR-sensitive mutant lung adenocarcinoma.

Abstract

The overexpression of hepatic growth factor(HGF) is one of the important reasons for the development of gefitinib resistance in EGFR-sensitive mutant lung adenocarcinoma cells. Targeting the HGF receptor MET through endocytosis inhibition or degradation induction has been proposed as a potential strategy to overcome this resistance. However, the effectiveness of this approach remains needs to be evaluated. In this study, we observed that MET receptors undergo persistent endocytosis but rarely enter the degradation pathway in HGF-overexpressing cells. We showed that MET endocytosis can be inhibited by using gene silence method or MET inhibitors. CHC or DNM2 gene silence slightly increases the sensitivity of resistant cells to gefitinib without affecting MET activity, while GRB2 gene silence can simultaneously inhibit MET endocytosis and reduce MET activity, resulting in a significant reversal effect of gefitinib resistance. Similarly, MET inhibitors significantly reverse drug resistance, accompanied by simultaneous inhibition of MET endocytosis and activity, highlighting the importance of both endocytosis and activity in HGF-induced gefitinib resistance. Additionally, we demonstrated that promoting MET degradation through deubiquitinase (USP8 or USP32) gene silence is another effective method for reversing drug resistance. Overall, our findings suggest that targeting MET receptor endocytosis and degradation is an attractive strategy for overcoming HGF-induced gefitinib resistance in EGFR-sensitive mutant lung adenocarcinoma.

• Authors: Demin Jiao, Yu Chen, Xiang Liu, Xiali Tang, Jun Chen, Yongyang Liu, Chunyan Jiang, Qingyong Chen
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 682 Pg. 371-380 (11 19 2023) ISSN: 1090-2104 [Electronic] United States
• PMID: 37844446 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 Elsevier Inc. All rights reserved.

Chemical References

• Gefitinib
• Quinazolines
• ErbB Receptors
• Hepatocyte Growth Factor
• Protein Kinase Inhibitors
• HGF protein, human
• EGFR protein, human

Topics

• Humans
• Gefitinib (pharmacology)
• Lung Neoplasms (drug therapy, genetics, metabolism)
• Quinazolines (pharmacology)
• ErbB Receptors (metabolism)
• Hepatocyte Growth Factor (genetics, pharmacology, metabolism)
• Drug Resistance, Neoplasm (genetics)
• Cell Line, Tumor
• Adenocarcinoma of Lung (drug therapy, genetics)
• Endocytosis
• Protein Kinase Inhibitors (pharmacology)