Antitumor Activity of a Novel Fibroblast Growth Factor Receptor Inhibitor for Intrahepatic Cholangiocarcinoma

  • Am J Pathol. 2019 Oct;189(10):2090-2101. doi: 10.1016/j.ajpath.2019.06.007.
Chiara Raggi  1 ,  Karim Fiaccadori  2 ,  Mirella Pastore  3 ,  Margherita Correnti  2 ,  Benedetta Piombanti  3 ,  Elisa Forti  2 ,  Nadia Navari  3 ,  Giovanni Abbadessa  4 ,  Terence Hall  4 ,  Annarita Destro  5 ,  Luca Di Tommaso  6 ,  Massimo Roncalli  6 ,  Fanyin Meng  7 ,  Shannon Glaser  7 ,  Elisabetta Rovida  8 ,  Caterina Peraldo-Neia  9 ,  Paula Olaizola  10 ,  Jesus M Banales  10 ,  Alessio Gerussi  11 ,  Alessandra Elvevi  11 ,  Michele Droz Dit Busset  12 ,  Sherrie Bhoori  13 ,  Vincenzo Mazzaferro  14 ,  Gianfranco Alpini  7 ,  Fabio Marra  3 ,  Pietro Invernizzi  15
Affiliations
  • 1. Humanitas Clinical and Research Center, Rozzano, Italy; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy. Electronic address: [email protected].
  • 2. Humanitas Clinical and Research Center, Rozzano, Italy.
  • 3. Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
  • 4. Clinical Development Department, ArQule, Inc., Burlington, Massachusetts.
  • 5. Pathology Unit, Humanitas Research Hospital, Rozzano, Italy.
  • 6. Pathology Unit, Humanitas Research Hospital, Rozzano, Italy; University of Milan Medical School, Milan, Italy.
  • 7. Department of Research, Central Texas Veterans Health Care System, Baylor Scott & White Digestive Disease Research Center, Scott & White Health, Department of Medical Physiology, Texas A&M University, College of Medicine, Temple, Texas.
  • 8. Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
  • 9. Cancer Genomics Laboratory, Fondazione Edo and Elvo Tempia, Biella, Italy.
  • 10. Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (Universidad del País Vasco/Euskal Herriko Unibertsitatea), Networked Biomedical Research Center for Hepatic and Digestive Diseases, Ikerbasque, San Sebastián, Spain.
  • 11. Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital, Department of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy.
  • 12. Hepato-Pancreato-Biliary Surgery and Liver Transplantation, IRCCS Foundation National Cancer Institute, Milan, Italy.
  • 13. Gastroenterology and Liver Transplant Hepatology, IRCCS Foundation National Cancer Institute, Milan, Italy.
  • 14. Hepato-Pancreato-Biliary Surgery and Liver Transplantation, IRCCS Foundation National Cancer Institute, Milan, Italy; Department of Surgery, University of Milan, Milan, Italy.
  • 15. Humanitas Clinical and Research Center, Rozzano, Italy; Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital, Department of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy. Electronic address: [email protected].
PMID: 31351075 DOI: 10.1016/j.ajpath.2019.06.007
Abstract

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.

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