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 S Torbenson; Benjamin R Kipp; Jie Zhou; Michael T Barrett; Michael P Gustafson; Steven R Alberts; Mitesh J Borad; Lewis R Roberts

doi:10.1016/j.canlet.2016.05.017

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

Cancer Lett. 2016 Sep 28;380(1):163-73. doi: 10.1016/j.canlet.2016.05.017. Epub 2016 May 20.

Authors

Yu Wang¹, Xiwei Ding², Shaoqing Wang³, Catherine D Moser⁴, Hassan M Shaleh⁴, Essa A Mohamed⁴, Roongruedee Chaiteerakij⁴, Loretta K Allotey⁴, Gang Chen⁴, Katsuyuki Miyabe⁴, Melissa S McNulty⁵, Albert Ndzengue⁴, Emily G Barr Fritcher⁶, Ryan A Knudson⁶, Patricia T Greipp⁶, Karl J Clark⁵, Michael S Torbenson⁶, Benjamin R Kipp⁶, Jie Zhou⁷, Michael T Barrett⁸, Michael P Gustafson⁶, Steven R Alberts⁹, Mitesh J Borad⁸, Lewis R Roberts¹⁰

Affiliations

¹ Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China; Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Mayo Clinic Cancer Center, Rochester, MN, USA.
² Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Mayo Clinic Cancer Center, Rochester, MN, USA; Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
³ Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Mayo Clinic Cancer Center, Rochester, MN, USA; Department of Pathology, Qiqihar Medical University, Qiqihar, China.
⁴ Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Mayo Clinic Cancer Center, Rochester, MN, USA.
⁵ Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA.
⁶ Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA.
⁷ Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
⁸ Division of Hematology and Medical Oncology, Mayo Clinic College of Medicine, Phoenix, AZ, USA.
⁹ Department of Medical Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA.
¹⁰ Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Mayo Clinic Cancer Center, Rochester, MN, USA. Electronic address: roberts.lewis@mayo.edu.

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.

Keywords: BGJ398; Dovitinib; FGFR2 fusion; Intrahepatic cholangiocarcinoma; Ponatinib.

Publication types

Comparative Study

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Benzimidazoles / pharmacology
Bile Duct Neoplasms / drug therapy*
Bile Duct Neoplasms / genetics
Bile Duct Neoplasms / metabolism
Bile Duct Neoplasms / pathology
Cell Proliferation / drug effects
Cholangiocarcinoma / drug therapy*
Cholangiocarcinoma / genetics
Cholangiocarcinoma / metabolism
Cholangiocarcinoma / secondary
Cytoskeletal Proteins / genetics
Cytoskeletal Proteins / metabolism*
Gene Fusion*
Humans
Imidazoles / pharmacology
Interleukin Receptor Common gamma Subunit / deficiency
Interleukin Receptor Common gamma Subunit / genetics
Lung Neoplasms / drug therapy*
Lung Neoplasms / genetics
Lung Neoplasms / metabolism
Lung Neoplasms / secondary
Matrix Metalloproteinase 2 / metabolism
Matrix Metalloproteinase 3 / metabolism
Matrix Metalloproteinase 9 / metabolism
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
Phenylurea Compounds / pharmacology*
Pyridazines / pharmacology
Pyrimidines / pharmacology*
Quinolones / pharmacology
Receptor, Fibroblast Growth Factor, Type 2 / antagonists & inhibitors*
Receptor, Fibroblast Growth Factor, Type 2 / genetics
Receptor, Fibroblast Growth Factor, Type 2 / metabolism*
Signal Transduction / drug effects
Time Factors
Tumor Burden / drug effects
Xenograft Model Antitumor Assays

Substances

4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one
Antineoplastic Agents
Benzimidazoles
CCDC6 protein, human
Cytoskeletal Proteins
Il2rg protein, mouse
Imidazoles
Interleukin Receptor Common gamma Subunit
Phenylurea Compounds
Pyridazines
Pyrimidines
Quinolones
ponatinib
infigratinib
FGFR2 protein, human
Receptor, Fibroblast Growth Factor, Type 2
MMP3 protein, human
Matrix Metalloproteinase 3
MMP2 protein, human
Matrix Metalloproteinase 2
MMP9 protein, human
Matrix Metalloproteinase 9

Abstract

Publication types

MeSH terms

Substances

Grants and funding