PMID- 26916220
OWN - NLM
STAT- MEDLINE
DCOM- 20170908
LR  - 20200923
IS  - 1098-2744 (Electronic)
IS  - 0899-1987 (Linking)
VI  - 56
IP  - 1
DP  - 2017 Jan
TI  - 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.
PG  - 106-117
LID - 10.1002/mc.22476 [doi]
AB  - 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. (c) 2016 Wiley 
      Periodicals, Inc.
CI  - (c) 2016 Wiley Periodicals, Inc.
FAU - Mizukami, Takuro
AU  - Mizukami T
AD  - Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, 
      Osaka, Japan.
AD  - Department of Clinical Oncology, St. Marianna University School of Medicine, 
      Kawasaki, Kanagawa, Japan.
FAU - Togashi, Yosuke
AU  - Togashi Y
AD  - Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, 
      Osaka, Japan.
FAU - Naruki, Saeko
AU  - Naruki S
AD  - Department of Pathology, St. Marianna University School of Medicine, Kawasaki, 
      Kanagawa, Japan.
FAU - Banno, Eri
AU  - Banno E
AD  - Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, 
      Osaka, Japan.
FAU - Terashima, Masato
AU  - Terashima M
AD  - Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, 
      Osaka, Japan.
FAU - de Velasco, Marco A
AU  - de Velasco MA
AD  - Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, 
      Osaka, Japan.
FAU - Sakai, Kazuko
AU  - Sakai K
AD  - Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, 
      Osaka, Japan.
FAU - Yoneshige, Azusa
AU  - Yoneshige A
AD  - Department of Pathology, Kinki University School of Medicine, Osaka-Sayama, 
      Osaka, Japan.
FAU - Hayashi, Hidetoshi
AU  - Hayashi H
AD  - Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, 
      Osaka, Japan.
AD  - Department of Medical Oncology, Kinki University School of Medicine, 
      Osaka-Sayama, Osaka, Japan.
FAU - Fujita, Yoshihiko
AU  - Fujita Y
AD  - Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, 
      Osaka, Japan.
FAU - Tomida, Shuta
AU  - Tomida S
AD  - Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, 
      Osaka, Japan.
FAU - Nakajima, Takako Eguchi
AU  - Nakajima TE
AD  - Department of Clinical Oncology, St. Marianna University School of Medicine, 
      Kawasaki, Kanagawa, Japan.
FAU - Fujino, Takashi
AU  - Fujino T
AD  - Department of Pathology, St. Marianna University School of Medicine, Kawasaki, 
      Kanagawa, Japan.
FAU - Boku, Narikazu
AU  - Boku N
AD  - Department of Clinical Oncology, St. Marianna University School of Medicine, 
      Kawasaki, Kanagawa, Japan.
FAU - Ito, Akihiko
AU  - Ito A
AD  - Department of Pathology, Kinki University School of Medicine, Osaka-Sayama, 
      Osaka, Japan.
FAU - Nakagawa, Kazuhiko
AU  - Nakagawa K
AD  - Department of Medical Oncology, Kinki University School of Medicine, 
      Osaka-Sayama, Osaka, Japan.
FAU - Nishio, Kazuto
AU  - Nishio K
AD  - Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, 
      Osaka, Japan.
LA  - eng
PT  - Journal Article
DEP - 20160224
PL  - United States
TA  - Mol Carcinog
JT  - Molecular carcinogenesis
JID - 8811105
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Fgf9 protein, mouse)
RN  - 0 (Fibroblast Growth Factor 9)
RN  - 0 (Phenylurea Compounds)
RN  - 0 (Pyrimidines)
RN  - 0 (Receptors, Fibroblast Growth Factor)
RN  - A4055ME1VK (infigratinib)
RN  - EC 2.7.10.1 (ErbB Receptors)
SB  - IM
MH  - Aged
MH  - Animals
MH  - Antineoplastic Agents/pharmacology/*therapeutic use
MH  - Colon/drug effects/metabolism/pathology
MH  - Colorectal Neoplasms/*drug therapy/*genetics/pathology
MH  - *Drug Resistance, Neoplasm/drug effects
MH  - ErbB Receptors/*antagonists & inhibitors
MH  - Female
MH  - Fibroblast Growth Factor 9/*genetics
MH  - Humans
MH  - Male
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Middle Aged
MH  - Phenylurea Compounds/pharmacology/therapeutic use
MH  - Pyrimidines/pharmacology/therapeutic use
MH  - Receptors, Fibroblast Growth Factor/antagonists & inhibitors
MH  - Rectum/drug effects/metabolism/pathology
MH  - Up-Regulation
OTO - NOTNLM
OT  - FGF9
OT  - KRAS
OT  - anti-EGFR therapy
OT  - colorectal cancer
OT  - drug resistance
EDAT- 2016/02/27 06:00
MHDA- 2017/09/09 06:00
CRDT- 2016/02/27 06:00
PHST- 2015/11/26 00:00 [received]
PHST- 2016/01/31 00:00 [revised]
PHST- 2016/02/06 00:00 [accepted]
PHST- 2016/02/27 06:00 [pubmed]
PHST- 2017/09/09 06:00 [medline]
PHST- 2016/02/27 06:00 [entrez]
AID - 10.1002/mc.22476 [doi]
PST - ppublish
SO  - Mol Carcinog. 2017 Jan;56(1):106-117. doi: 10.1002/mc.22476. Epub 2016 Feb 24.