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

Takuro Mizukami, Yosuke Togashi, Saeko Naruki, Eri Banno, Masato Terashima, Marco A. de Velasco, Kazuko Sakai, Azusa Yoneshige, Hidetoshi Hayashi, Yoshihiko Fujita, Shuta Tomida, Takako Eguchi Nakajima, Takashi Fujino, Narikazu Boku, Akihiko Ito, Kazuhiko Nakagawa, Kazuto Nishio

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish
JournalMolecular Carcinogenesis
DOIs
Publication statusAccepted/In press - 2016
Externally publishedYes

Fingerprint

Colorectal Neoplasms
Up-Regulation
Genes
Therapeutics
Fibroblast Growth Factors
Fluorescence In Situ Hybridization
Immunohistochemistry
Cell Line
Messenger RNA
Neoplasms
Proteins

Keywords

  • Anti-EGFR therapy
  • Colorectal cancer
  • Drug resistance
  • FGF9
  • KRAS

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Biology

Cite this

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. / Mizukami, Takuro; Togashi, Yosuke; Naruki, Saeko; Banno, Eri; Terashima, Masato; de Velasco, Marco A.; Sakai, Kazuko; Yoneshige, Azusa; Hayashi, Hidetoshi; Fujita, Yoshihiko; Tomida, Shuta; Nakajima, Takako Eguchi; Fujino, Takashi; Boku, Narikazu; Ito, Akihiko; Nakagawa, Kazuhiko; Nishio, Kazuto.

In: Molecular Carcinogenesis, 2016.

Research output: Contribution to journalArticle

Mizukami, T, Togashi, Y, Naruki, S, Banno, E, Terashima, M, de Velasco, MA, Sakai, K, Yoneshige, A, Hayashi, H, Fujita, Y, Tomida, S, Nakajima, TE, Fujino, T, Boku, N, Ito, A, Nakagawa, K & Nishio, K 2016, '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', Molecular Carcinogenesis. https://doi.org/10.1002/mc.22476
Mizukami, Takuro ; Togashi, Yosuke ; Naruki, Saeko ; Banno, Eri ; Terashima, Masato ; de Velasco, Marco A. ; Sakai, Kazuko ; Yoneshige, Azusa ; Hayashi, Hidetoshi ; Fujita, Yoshihiko ; Tomida, Shuta ; Nakajima, Takako Eguchi ; Fujino, Takashi ; Boku, Narikazu ; Ito, Akihiko ; Nakagawa, Kazuhiko ; Nishio, Kazuto. / 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. In: Molecular Carcinogenesis. 2016.
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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.",
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T2 - A subset of colorectal cancer patients with FGF9 upregulation may be resistant to anti-EGFR therapies

AU - Mizukami, Takuro

AU - Togashi, Yosuke

AU - Naruki, Saeko

AU - Banno, Eri

AU - Terashima, Masato

AU - de Velasco, Marco A.

AU - Sakai, Kazuko

AU - Yoneshige, Azusa

AU - Hayashi, Hidetoshi

AU - Fujita, Yoshihiko

AU - Tomida, Shuta

AU - Nakajima, Takako Eguchi

AU - Fujino, Takashi

AU - Boku, Narikazu

AU - Ito, Akihiko

AU - Nakagawa, Kazuhiko

AU - Nishio, Kazuto

PY - 2016

Y1 - 2016

N2 - 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.

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.

KW - Anti-EGFR therapy

KW - Colorectal cancer

KW - Drug resistance

KW - FGF9

KW - KRAS

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