Antitumor effect of FGFR inhibitors on a novel cholangiocarcinoma patient derived xenograft mouse model endogenously expressing an FGFR2-CCDC6 fusion protein

Yu Wang, Xiwei Ding, Shaoqing Wang, Catherine D. Moser, Hassan M. Shaleh, Essa A. Mohamed, Roongruedee Chaiteerakij, Loretta K. Allotey, Gang Chen, Katsuyuki Miyabe, Melissa S. McNulty, Albert Ndzengue, Emily G. Barr Fritcher, Ryan A. Knudson, Patricia T Greipp, Karl J Clark, Michael Torbenson, Benjamin R. Kipp, Jie Zhou, Michael BarrettMichael Gustafson, Steven Robert Alberts, Mitesh J Borad, Lewis Rowland Roberts

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Cholangiocarcinoma is a highly lethal cancer with limited therapeutic options. Recent genomic analysis of cholangiocarcinoma has revealed the presence of fibroblast growth factor receptor 2 (FGFR2) fusion proteins in up to 13% of intrahepatic cholangiocarcinoma (iCCA). FGFR fusions have been identified as a novel oncogenic and druggable target in a number of cancers. In this study, we established a novel cholangiocarcinoma patient derived xenograft (PDX) mouse model bearing an FGFR2-CCDC6 fusion protein from a metastatic lung nodule of an iCCA patient. Using this PDX model, we confirmed the ability of the FGFR inhibitors, ponatinib, dovitinib and BGJ398, to modulate FGFR signaling, inhibit cell proliferation and induce cell apoptosis in cholangiocarcinoma tumors harboring FGFR2 fusions. In addition, BGJ398 appeared to be superior in potency to ponatinib and dovitinib in this model. Our findings provide a strong rationale for the investigation of FGFR inhibitors, particularly BGJ398, as a therapeutic option for cholangiocarcinoma patients harboring FGFR2 fusions.

Original languageEnglish (US)
Pages (from-to)163-173
Number of pages11
JournalCancer Letters
Volume380
Issue number1
DOIs
StatePublished - Sep 28 2016

Fingerprint

Receptor, Fibroblast Growth Factor, Type 2
Cholangiocarcinoma
Heterografts
Proteins
Neoplasms
Cell Proliferation
Apoptosis
Lung
Therapeutics

Keywords

  • BGJ398
  • Dovitinib
  • FGFR2 fusion
  • Intrahepatic cholangiocarcinoma
  • Ponatinib

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cancer Research

Cite this

Antitumor effect of FGFR inhibitors on a novel cholangiocarcinoma patient derived xenograft mouse model endogenously expressing an FGFR2-CCDC6 fusion protein. / Wang, Yu; Ding, Xiwei; Wang, Shaoqing; Moser, Catherine D.; Shaleh, Hassan M.; Mohamed, Essa A.; Chaiteerakij, Roongruedee; Allotey, Loretta K.; Chen, Gang; Miyabe, Katsuyuki; McNulty, Melissa S.; Ndzengue, Albert; Barr Fritcher, Emily G.; Knudson, Ryan A.; Greipp, Patricia T; Clark, Karl J; Torbenson, Michael; Kipp, Benjamin R.; Zhou, Jie; Barrett, Michael; Gustafson, Michael; Alberts, Steven Robert; Borad, Mitesh J; Roberts, Lewis Rowland.

In: Cancer Letters, Vol. 380, No. 1, 28.09.2016, p. 163-173.

Research output: Contribution to journalArticle

Wang, Y, Ding, X, Wang, S, Moser, CD, Shaleh, HM, Mohamed, EA, Chaiteerakij, R, Allotey, LK, Chen, G, Miyabe, K, McNulty, MS, Ndzengue, A, Barr Fritcher, EG, Knudson, RA, Greipp, PT, Clark, KJ, Torbenson, M, Kipp, BR, Zhou, J, Barrett, M, Gustafson, M, Alberts, SR, Borad, MJ & Roberts, LR 2016, 'Antitumor effect of FGFR inhibitors on a novel cholangiocarcinoma patient derived xenograft mouse model endogenously expressing an FGFR2-CCDC6 fusion protein', Cancer Letters, vol. 380, no. 1, pp. 163-173. https://doi.org/10.1016/j.canlet.2016.05.017
Wang, Yu ; Ding, Xiwei ; Wang, Shaoqing ; Moser, Catherine D. ; Shaleh, Hassan M. ; Mohamed, Essa A. ; Chaiteerakij, Roongruedee ; Allotey, Loretta K. ; Chen, Gang ; Miyabe, Katsuyuki ; McNulty, Melissa S. ; Ndzengue, Albert ; Barr Fritcher, Emily G. ; Knudson, Ryan A. ; Greipp, Patricia T ; Clark, Karl J ; Torbenson, Michael ; Kipp, Benjamin R. ; Zhou, Jie ; Barrett, Michael ; Gustafson, Michael ; Alberts, Steven Robert ; Borad, Mitesh J ; Roberts, Lewis Rowland. / Antitumor effect of FGFR inhibitors on a novel cholangiocarcinoma patient derived xenograft mouse model endogenously expressing an FGFR2-CCDC6 fusion protein. In: Cancer Letters. 2016 ; Vol. 380, No. 1. pp. 163-173.
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abstract = "Cholangiocarcinoma is a highly lethal cancer with limited therapeutic options. Recent genomic analysis of cholangiocarcinoma has revealed the presence of fibroblast growth factor receptor 2 (FGFR2) fusion proteins in up to 13{\%} of intrahepatic cholangiocarcinoma (iCCA). FGFR fusions have been identified as a novel oncogenic and druggable target in a number of cancers. In this study, we established a novel cholangiocarcinoma patient derived xenograft (PDX) mouse model bearing an FGFR2-CCDC6 fusion protein from a metastatic lung nodule of an iCCA patient. Using this PDX model, we confirmed the ability of the FGFR inhibitors, ponatinib, dovitinib and BGJ398, to modulate FGFR signaling, inhibit cell proliferation and induce cell apoptosis in cholangiocarcinoma tumors harboring FGFR2 fusions. In addition, BGJ398 appeared to be superior in potency to ponatinib and dovitinib in this model. Our findings provide a strong rationale for the investigation of FGFR inhibitors, particularly BGJ398, as a therapeutic option for cholangiocarcinoma patients harboring FGFR2 fusions.",
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AU - Wang, Yu

AU - Ding, Xiwei

AU - Wang, Shaoqing

AU - Moser, Catherine D.

AU - Shaleh, Hassan M.

AU - Mohamed, Essa A.

AU - Chaiteerakij, Roongruedee

AU - Allotey, Loretta K.

AU - Chen, Gang

AU - Miyabe, Katsuyuki

AU - McNulty, Melissa S.

AU - Ndzengue, Albert

AU - Barr Fritcher, Emily G.

AU - Knudson, Ryan A.

AU - Greipp, Patricia T

AU - Clark, Karl J

AU - Torbenson, Michael

AU - Kipp, Benjamin R.

AU - Zhou, Jie

AU - Barrett, Michael

AU - Gustafson, Michael

AU - Alberts, Steven Robert

AU - Borad, Mitesh J

AU - Roberts, Lewis Rowland

PY - 2016/9/28

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N2 - Cholangiocarcinoma is a highly lethal cancer with limited therapeutic options. Recent genomic analysis of cholangiocarcinoma has revealed the presence of fibroblast growth factor receptor 2 (FGFR2) fusion proteins in up to 13% of intrahepatic cholangiocarcinoma (iCCA). FGFR fusions have been identified as a novel oncogenic and druggable target in a number of cancers. In this study, we established a novel cholangiocarcinoma patient derived xenograft (PDX) mouse model bearing an FGFR2-CCDC6 fusion protein from a metastatic lung nodule of an iCCA patient. Using this PDX model, we confirmed the ability of the FGFR inhibitors, ponatinib, dovitinib and BGJ398, to modulate FGFR signaling, inhibit cell proliferation and induce cell apoptosis in cholangiocarcinoma tumors harboring FGFR2 fusions. In addition, BGJ398 appeared to be superior in potency to ponatinib and dovitinib in this model. Our findings provide a strong rationale for the investigation of FGFR inhibitors, particularly BGJ398, as a therapeutic option for cholangiocarcinoma patients harboring FGFR2 fusions.

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