Targeting FGFR2 with alofanib (RPT835) shows potent activity in tumour models

• Published in: European journal of cancer (1990) 2016-07, Vol.61, p.20-28
• Main Authors: Tsimafeyeu, Ilya, Ludes-Meyers, John, Stepanova, Evgenia, Daeyaert, Frits, Kochenkov, Dmitry, Joose, Jean-Baptiste, Solomko, Eliso, Van Akene, Koen, Peretolchina, Nina, Yin, Wei, Ryabaya, Oxana, Byakhov, Mikhail, Tjulandin, Sergei
• Format: Article
• Language: English
• Subjects: Allosteric inhibitor; Alofanib; Angiogenesis Inhibitors - pharmacology; Animals; Antineoplastic Agents - pharmacology; Benzoates - pharmacology; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Disease Models, Animal; Endothelial Cells - drug effects; Fibroblast growth factor receptor 2; Hematology, Oncology and Palliative Medicine; Human Umbilical Vein Endothelial Cells - drug effects; Humans; Mice; Molecular Targeted Therapy - methods; Preclinical studies; Receptor, Fibroblast Growth Factor, Type 2 - antagonists & inhibitors; RPT835; Sulfonamides - pharmacology; Xenograft Model Antitumor Assays
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2016.03.068

Abstract Alofanib (RPT835) is a novel selective allosteric inhibitor of fibroblast growth factor receptor 2 (FGFR2). We showed previously that alofanib could bind to the extracellular domain of FGFR2 and has an inhibitory effect on FGF2-induced phoshphorylation of FRS2α. In the present study, we further showed that alofanib inhibited phosphorylation of FRS2α with the half maximal inhibitory concentration (IC50) values of 7 and 9 nmol/l in cancer cells expressing different FGFR2 isoforms. In a panel of four cell lines representing several tumour types (triple-negative breast cancer, melanoma, and ovarian cancer), alofanib inhibited FGF-mediated proliferation with 50% growth inhibition (GI50) values of 16–370 nmol/l. Alofanib dose dependently inhibited the proliferation and migration of human and mouse endothelial cells (GI50 11–58 nmol/l) compared with brivanib and bevacizumab. Treatment with alofanib ablated experimental FGF-induced angiogenesis in vivo . In a FGFR-driven human tumour xenograft model, oral administration of alofanib was well tolerated and resulted in potent antitumour activity. Importantly, alofanib was effective in FGFR2-expressing models. These results show that alofanib is a potent FGFR2 inhibitor and provide strong rationale for its evaluation in patients with FGFR2-driven cancers.