title: FGFR2-amplified gastric cancer cell lines require FGFR2 and Erbb3 signaling for growth and survival.
abstract: We have identified a critical role for amplified FGFR2 in gastric cancer cell proliferation and survival. In a panel of gastric cancer cell lines, fibroblast growth factor receptor 2 (FGFR2) was overexpressed and tyrosine phosphorylated selectively in FGFR2-amplified cell lines KatoIII, Snu16, and OCUM-2M. FGFR2 kinase inhibition by a specific small-molecule inhibitor resulted in selective and potent growth inhibition in FGFR2-amplified cell lines, resulting in growth arrest in KatoIII cells and prominent induction of apoptosis in both Snu16 and OCUM-2M cells. FGFR2-amplified cell lines also contained elevated phosphotyrosine in EGFR, Her2, and Erbb3, but the elevated phosphorylation in EGFR could not be inhibited by gefitinib or erlotinib. We show that the elevated EGFR, Her2, and Erbb3 phosphotyrosine is dependent on FGFR2, revealing EGFR family kinases to be downstream targets of amplified FGFR2. Moreover, shRNA to Erbb3 resulted in a loss of proliferation, confirming a functional role for the activated EGFR signaling pathway. These results reveal that both the FGFR2 and EGFR family signaling pathways are activated in FGFR2-amplified gastric cancer cell lines to drive cell proliferation and survival. Inhibitors of FGFR2 or Erbb3 signaling may have therapeutic efficacy in the subset of gastric cancers containing FGFR2 amplification.
authors.affiliation: Pharmacology, Merck Research Laboratories, Boston, MA 02115, USA.
authors.forename: Kaiko
authors.initials: K
authors.lastname: Kunii
authors.forename: Lenora
authors.initials: L
authors.lastname: Davis
authors.forename: Julie
authors.initials: J
authors.lastname: Gorenstein
authors.forename: Harold
authors.initials: H
authors.lastname: Hatch
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yashiro
authors.forename: Alessandra
authors.initials: A
authors.lastname: Di Bacco
authors.forename: Cem
authors.initials: C
authors.lastname: Elbi
authors.forename: Bart
authors.initials: B
authors.lastname: Lutterbach
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D005784:Gene Amplification; D006801:Humans; D010766:Phosphorylation; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D020893:Receptor, ErbB-3 / Q000378:metabolism*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology
chemical_list: C115711:PD 173074; D011743:Pyrimidines; D034741:RNA, Small Interfering; D020893:Receptor, ErbB-3; D051497:Receptor, Fibroblast Growth Factor, Type 2