title: Neighbors' death is required for surviving human adenocarcinoma PC-9 cells in an early stage of gefitinib treatment.
abstract: Acquired drug resistance is a major problem in chemotherapy, and understanding of the mechanism, by which naïve cells defend themselves from drugs when the cells exposed to the drugs for the first time, may provide a solution of the problem. Gefitinib is an epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor, and used as an anticancer drug; however, gefitinib treatment may sometimes lead cancer cells gradually into a gefitinib-tolerance. Here we describe that human adenocarcinoma PC-9 cells even under the presence of gefitinib were able to survive by activating another signaling pathway involving fibroblast growth factor receptor (FGFR) and its signaling molecule, FGF2; and further suggest that the FGF2 for initiating the pathway might be supplied from neighboring cells which were killed by gefitinib, i.e., the survival might be founded on neighbors' sacrifice in an early stage of gefitinib treatment. Our findings suggested that whether cells had a chance to encounter to survival factors such as FGF2 soon after gefitinib treatment might be an important crossroads for the cells for survival and for gaining a gefitinib tolerance.
authors.affiliation: Department of Molecular Pharmacology, National Institute of Neuroscience, NCNP, Kodaira, Tokyo, Japan; Division of RNA Medical Science, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Department of Molecular Pharmacology, National Institute of Neuroscience, NCNP, Kodaira, Tokyo, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukuoka
authors.affiliation: Division of Molecular Cell Signaling, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Katsuji
authors.initials: K
authors.lastname: Yoshioka
authors.affiliation: Department of Molecular Pharmacology, National Institute of Neuroscience, NCNP, Kodaira, Tokyo, Japan. Electronic address: hohjohh@ncnp.go.jp.
authors.forename: Hirohiko
authors.initials: H
authors.lastname: Hohjoh
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology; D016923:Cell Death; D045744:Cell Line, Tumor; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D000077156:Gefitinib; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D011799:Quinazolines / Q000494:pharmacology*; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D015398:Signal Transduction; D016896:Treatment Outcome
chemical_list: D011799:Quinazolines; D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: Epidermal growth factor receptor (EGFR); FGF2; Fibroblast growth factor receptor (FGFR); Gefitinib; Gefitinib resistance; PC-9 cells