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

• Published in: Biochemical and biophysical research communications Vol. 458; no. 4; pp. 856 - 861
• Main Authors: Refaat, Alaa, Aminullah, Zhou, Yue, Kawanishi, Miho, Tomaru, Rika, Abdelhamed, Sherif, Shin, Myoung-Sook, Koizumi, Keiichi, Yokoyama, Satoru, Saiki, Ikuo, Sakurai, Hiroaki
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.03.2015
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Cisplatin; Cisplatin - pharmacology; Drug Resistance, Neoplasm; EGFR; Humans; Lung - drug effects; Lung - metabolism; Lung - pathology; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; MAP Kinase Signaling System - drug effects; MAPK; Mutation; NSCLC; Phosphorylation - drug effects; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; NSCLC; MAPK; Cisplatin; EGFR; Apoptosis
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2015.02.044

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. •Cisplatin induces Ser/Thr phosphorylation of wild type EGFR via MAPKs.•EGFR with active mutation is also phosphorylated by cisplatin in lung cancer cells.•Cisplatin causes downregulation of EGFR tyrosine phosphorylation via ERK pathway.•Internalization is switched to a p38-dependent mechanism by cisplatin treatment.•p38 inhibitor enhances cisplatin-induced apoptotic cell death.