title: Antitumor effect of FGFR inhibitors on a novel cholangiocarcinoma patient derived xenograft mouse model endogenously expressing an FGFR2-CCDC6 fusion protein.
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.
authors.affiliation: 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.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Xiwei
authors.initials: X
authors.lastname: Ding
authors.affiliation: 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.
authors.forename: Shaoqing
authors.initials: S
authors.lastname: Wang
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Mayo Clinic Cancer Center, Rochester, MN, USA.
authors.forename: Catherine D
authors.initials: CD
authors.lastname: Moser
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Mayo Clinic Cancer Center, Rochester, MN, USA.
authors.forename: Hassan M
authors.initials: HM
authors.lastname: Shaleh
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Mayo Clinic Cancer Center, Rochester, MN, USA.
authors.forename: Essa A
authors.initials: EA
authors.lastname: Mohamed
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Mayo Clinic Cancer Center, Rochester, MN, USA.
authors.forename: Roongruedee
authors.initials: R
authors.lastname: Chaiteerakij
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Mayo Clinic Cancer Center, Rochester, MN, USA.
authors.forename: Loretta K
authors.initials: LK
authors.lastname: Allotey
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Mayo Clinic Cancer Center, Rochester, MN, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Mayo Clinic Cancer Center, Rochester, MN, USA.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Miyabe
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Melissa S
authors.initials: MS
authors.lastname: McNulty
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Mayo Clinic Cancer Center, Rochester, MN, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Ndzengue
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Emily G
authors.initials: EG
authors.lastname: Barr Fritcher
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Knudson
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Patricia T
authors.initials: PT
authors.lastname: Greipp
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Clark
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Torbenson
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Kipp
authors.affiliation: Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Division of Hematology and Medical Oncology, Mayo Clinic College of Medicine, Phoenix, AZ, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Barrett
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Gustafson
authors.affiliation: Department of Medical Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Alberts
authors.affiliation: Division of Hematology and Medical Oncology, Mayo Clinic College of Medicine, Phoenix, AZ, USA.
authors.forename: Mitesh J
authors.initials: MJ
authors.lastname: Borad
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Mayo Clinic Cancer Center, Rochester, MN, USA. Electronic address: roberts.lewis@mayo.edu.
authors.forename: Lewis R
authors.initials: LR
authors.lastname: Roberts
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D050939:Gene Fusion; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D000970:Antineoplastic Agents; D001562:Benzimidazoles; C088832:CCDC6 protein, human; D003598:Cytoskeletal Proteins; C507942:Il2rg protein, mouse; D007093:Imidazoles; D053631:Interleukin Receptor Common gamma Subunit; D010671:Phenylurea Compounds; D011724:Pyridazines; D011743:Pyrimidines; D015363:Quinolones; C545373:ponatinib; C568950:infigratinib; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: BGJ398; Dovitinib; FGFR2 fusion; Intrahepatic cholangiocarcinoma; Ponatinib