TY - JOUR
T1 - Antitumor Activity of a Novel Fibroblast Growth Factor Receptor Inhibitor for Intrahepatic Cholangiocarcinoma
AU - Raggi, Chiara
AU - Fiaccadori, Karim
AU - Pastore, Mirella
AU - Correnti, Margherita
AU - Piombanti, Benedetta
AU - Forti, Elisa
AU - Navari, Nadia
AU - Abbadessa, Giovanni
AU - Hall, Terence
AU - Destro, Annarita
AU - Di Tommaso, Luca
AU - Roncalli, Massimo
AU - Meng, Fanyin
AU - Glaser, Shannon
AU - Rovida, Elisabetta
AU - Peraldo-Neia, Caterina
AU - Olaizola, Paula
AU - Banales, Jesus M.
AU - Gerussi, Alessio
AU - Elvevi, Alessandra
AU - Droz dit Busset, Michele
AU - Bhoori, Sherrie
AU - Mazzaferro, Vincenzo
AU - Alpini, Gianfranco
AU - Marra, Fabio
AU - Invernizzi, Pietro
PY - 2019/10
Y1 - 2019/10
N2 - Fibroblast growth factor receptor 2 (FGFR2) might have an important role in the pathogenesis and biology of cholangiocarcinoma (CCA). We examined FGFR expression in CCA tumor specimens obtained from patients and CCA cell lines, and then determined the effects of the novel FGFR inhibitor, derazantinib (DZB; formally, ARQ 087), which is currently in clinical phase 2 trials for intrahepatic CCA. DZB inhibited the growth of CCA cell lines in a dose-dependent manner, and extracellular signal-regulated kinase 1/2 and AKT. It also activated apoptotic and cell growth arrest signaling. DZB reduced the in vitro invasiveness and the expression of key epithelial-mesenchymal transition genes. The in vitro data correlated with the expression of FGFRs in human CCA specimens by immunohistochemistry (FGFR1, 30% positive; and FGFR2, 65% positive) and the CCA cell lines assayed by Western blot analysis. These correlated in vitro studies suggest that FGFR may play an important role in the pathogenesis and biology of CCA. Our findings support the notion that FGFR inhibitors, like DZB, should be further evaluated at the clinical stage as targeted therapy for CCA treatment.
AB - Fibroblast growth factor receptor 2 (FGFR2) might have an important role in the pathogenesis and biology of cholangiocarcinoma (CCA). We examined FGFR expression in CCA tumor specimens obtained from patients and CCA cell lines, and then determined the effects of the novel FGFR inhibitor, derazantinib (DZB; formally, ARQ 087), which is currently in clinical phase 2 trials for intrahepatic CCA. DZB inhibited the growth of CCA cell lines in a dose-dependent manner, and extracellular signal-regulated kinase 1/2 and AKT. It also activated apoptotic and cell growth arrest signaling. DZB reduced the in vitro invasiveness and the expression of key epithelial-mesenchymal transition genes. The in vitro data correlated with the expression of FGFRs in human CCA specimens by immunohistochemistry (FGFR1, 30% positive; and FGFR2, 65% positive) and the CCA cell lines assayed by Western blot analysis. These correlated in vitro studies suggest that FGFR may play an important role in the pathogenesis and biology of CCA. Our findings support the notion that FGFR inhibitors, like DZB, should be further evaluated at the clinical stage as targeted therapy for CCA treatment.
U2 - 10.1016/j.ajpath.2019.06.007
DO - 10.1016/j.ajpath.2019.06.007
M3 - Article
VL - 189
SP - 2090
EP - 2101
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 10
ER -