title: Significance of FGF9 gene in resistance to anti-EGFR therapies targeting colorectal cancer: A subset of colorectal cancer patients with FGF9 upregulation may be resistant to anti-EGFR therapies.
abstract: Although fibroblast growth factor (FGF) signals are strongly associated with malignancy, limited information is available regarding the role of the FGF9 signal in colorectal cancer (CRC). In this study, we investigated the frequency of FGF9 amplification in CRC clinical specimens and the association between the FGF9 gene and resistance to anti-EGFR therapies. In clinical samples, an FGF9 copy number gain of >5 copies was observed at a frequency of 8/145 (5.5%) and tended to be related to wild-type KRAS (7/96, 7.3%). Furthermore, FGF9 amplification was not observed in any of the samples from the 15 responders to anti-EGFR therapies but was observed in one sample from the seven non-responders with wild-type KRAS, and two samples from non-responders also had high FGF9 mRNA expression levels. FGF9 amplification was validated using a fluorescence in situ hybridization (FISH) analysis, and FGF9-amplified sections showed readily detectable signals originating from FGF9 protein when examined using immunohistochemistry. In both the in vitro and in vivo experiments using FGF9-overexpressing CRC cell lines, FGF9 overexpression induced strong resistance to anti-EGFR therapies via the enforced FGFR signal, and this resistance was cancelled by the application of an FGFR inhibitor. Considering these results, the FGF9 gene may play an important role in resistance to anti-EGFR therapies in patients with CRC, and such resistance might be overcome by combined treatment with an anti-FGFR inhibitor. These findings strongly encourage the development of FGFR-targeted therapy for CRC patients with FGF9 gene upregulation. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.|Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
authors.forename: Takuro
authors.initials: T
authors.lastname: Mizukami
authors.affiliation: Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Togashi
authors.affiliation: Department of Pathology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
authors.forename: Saeko
authors.initials: S
authors.lastname: Naruki
authors.affiliation: Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Banno
authors.affiliation: Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Terashima
authors.affiliation: Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Marco A
authors.initials: MA
authors.lastname: de Velasco
authors.affiliation: Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Sakai
authors.affiliation: Department of Pathology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Azusa
authors.initials: A
authors.lastname: Yoneshige
authors.affiliation: Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.|Department of Medical Oncology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Hayashi
authors.affiliation: Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Fujita
authors.affiliation: Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Shuta
authors.initials: S
authors.lastname: Tomida
authors.affiliation: Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
authors.forename: Takako Eguchi
authors.initials: TE
authors.lastname: Nakajima
authors.affiliation: Department of Pathology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujino
authors.affiliation: Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
authors.forename: Narikazu
authors.initials: N
authors.lastname: Boku
authors.affiliation: Department of Pathology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Ito
authors.affiliation: Department of Medical Oncology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakagawa
authors.affiliation: Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
mesh_terms: D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D051525:Fibroblast Growth Factor 9 / Q000235:genetics*; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors; D012007:Rectum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; C496460:Fgf9 protein, mouse; D051525:Fibroblast Growth Factor 9; D010671:Phenylurea Compounds; D011743:Pyrimidines; D017468:Receptors, Fibroblast Growth Factor; C568950:infigratinib; D066246:ErbB Receptors
keywords: FGF9; KRAS; anti-EGFR therapy; colorectal cancer; drug resistance