title: 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.affiliation: Department of Cancer Cell Biology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan; Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan; Center for Aging and Associated Diseases, Zewail City of Science and Technology, 6th of October City, Giza 12588, Egypt.
authors.forename: Alaa
authors.initials: A
authors.lastname: Refaat
authors.affiliation: Department of Cancer Cell Biology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan.
authors.lastname: Aminullah
authors.affiliation: Department of Cancer Cell Biology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Kawanishi
authors.affiliation: Department of Cancer Cell Biology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan.
authors.forename: Rika
authors.initials: R
authors.lastname: Tomaru
authors.affiliation: Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan.
authors.forename: Sherif
authors.initials: S
authors.lastname: Abdelhamed
authors.affiliation: Department of Cancer Cell Biology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan; Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan.
authors.forename: Myoung-Sook
authors.initials: MS
authors.lastname: Shin
authors.affiliation: Division of Kampo Diagnostics, Institute of Natural Medicine, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Koizumi
authors.affiliation: Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Yokoyama
authors.affiliation: Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Saiki
authors.affiliation: Department of Cancer Cell Biology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan. Electronic address: hsakurai@pha.u-toyama.ac.jp.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Sakurai
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D002945:Cisplatin
keywords: Apoptosis; Cisplatin; EGFR; MAPK; NSCLC