Role of tyrosine kinase-independent phosphorylation of EGFR with activating mutation in cisplatin-treated lung cancer cells.

Abstract

Epidermal growth factor receptor (EGFR) mutation is one of the hallmarks of cancer progression and resistance to anticancer therapies, particularly non-small cell lung carcinomas (NSCLCs). In contrast to the canonical EGFR activation in which tyrosine residues are engaged, we have demonstrated that the non-canonical pathway is triggered by phosphorylation of serine and threonine residues through p38 and ERK MAPKs, respectively. The purpose of this study is to investigate the role of non-canonical EGFR pathway in resistance mechanism against cisplatin treatment. Wild type and mutated (exon 19 deletion) EGFR-expressing cells responded similarly to cisplatin by showing MAPK-mediated EGFR phosphorylation. It is interesting that internalization mechanism of EGFR was switched from tyrosine kinase-dependent to p38-dependent fashions, which is involved in a survival pathway that counteracts cisplatin treatment. We therefore introduce a potential combinatorial therapy composed of p38 inhibition and cisplatin to block the activation of EGFR, therefore inducing cancer cell death and apoptosis.

• Authors: Alaa Refaat, Aminullah, Yue Zhou, Miho Kawanishi, Rika Tomaru, Sherif Abdelhamed, Myoung-Sook Shin, Keiichi Koizumi, Satoru Yokoyama, Ikuo Saiki, Hiroaki Sakurai
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 458 Issue 4 Pg. 856-61 (Mar 20 2015) ISSN: 1090-2104 [Electronic] United States
• PMID: 25701783 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• ErbB Receptors
• Cisplatin

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, pathology)
• Cell Line, Tumor
• Cisplatin (pharmacology)
• Drug Resistance, Neoplasm
• ErbB Receptors (genetics, metabolism)
• Humans
• Lung (drug effects, metabolism, pathology)
• Lung Neoplasms (drug therapy, genetics, pathology)
• MAP Kinase Signaling System (drug effects)
• Mutation
• Phosphorylation (drug effects)