title: Activation of the FGF2-FGFR1 autocrine pathway: a novel mechanism of acquired resistance to gefitinib in NSCLC.
abstract: Patients with non-small cell lung cancer (NSCLC) that harbors epidermal growth factor receptor (EGFR) mutations initially respond to EGFR-tyrosine kinase inhibitors (TKI) but eventually experience relapse. Acquired resistance to EGFR-TKIs is strongly associated with patient mortality. Thus, elucidation of the mechanism of acquired resistance to EGFR-TKIs is of great importance. In this study, gefitinib-resistant cell line models were established by long-term exposure to gefitinib using the gefitinib-sensitive lung cancer cell lines, PC9 and HCC827. Expression analyses indicated that both FGFR1 and FGF2 were increased in PC9 gefitinib-resistant (PC9 GR) cells as compared with PC9 naïve (PC9 na) cells. Importantly, proliferation of gefitinib-resistant cells was dependent on the FGF2 -FGFR1 pathway. Mechanistically, inhibition of either FGF2 or FGFR1 by siRNA or FGFR inhibitor (PD173074) restored gefitinib sensitivity in PC9 GR cells. These data suggest that FGF2 -FGFR1 activation through an autocrine loop is a novel mechanism of acquired resistance to EGFR-TKIs.
authors.affiliation: Department of Pulmonary Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Terai
authors.forename: Kenzo
authors.initials: K
authors.lastname: Soejima
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yasuda
authors.forename: Sohei
authors.initials: S
authors.lastname: Nakayama
authors.forename: Junko
authors.initials: J
authors.lastname: Hamamoto
authors.forename: Daisuke
authors.initials: D
authors.lastname: Arai
authors.forename: Kota
authors.initials: K
authors.lastname: Ishioka
authors.forename: Keiko
authors.initials: K
authors.lastname: Ohgino
authors.forename: Shinnosuke
authors.initials: S
authors.lastname: Ikemura
authors.forename: Takashi
authors.initials: T
authors.lastname: Sato
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yoda
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Satomi
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Naoki
authors.forename: Tomoko
authors.initials: T
authors.lastname: Betsuyaku
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D019898:Autocrine Communication / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002999:Clone Cells; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms; D008954:Models, Biological; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C115711:PD 173074; D011743:Pyrimidines; D011799:Quinazolines; D034741:RNA, Small Interfering; D016222:Fibroblast Growth Factor 2; D066246:ErbB Receptors; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D000077156:Gefitinib