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|Ref Type||Journal Article|
|Authors||Tsimafeyeu I, Ludes-Meyers J, Stepanova E, Daeyaert F, Khochenkov D, Joose JB, Solomko E, Van Akene K, Peretolchina N, Yin W, Ryabaya O, Byakhov M, Tjulandin S|
|Title||Targeting FGFR2 with alofanib (RPT835) shows potent activity in tumour models.|
|Journal||European journal of cancer (Oxford, England : 1990)|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Alofanib||RPT 835|RPT-835|RPT 835|ES000835||FGFR2 Inhibitor 22||Alofanib (RPT835) is a small molecule that binds to the extracellular domain of Fgfr2 and inhibits downstream signaling, potentially resulting in decreased tumor cell proliferation (PMID: 27136102).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|FGFR2 positive||triple-receptor negative breast cancer||sensitive||Alofanib||Preclinical - Cell culture||Actionable||In a preclinical study, Alofanib (RPT835) treatment led to inhibition of cell proliferation in triple-receptor negative breast cancer cell lines expressing FGFR2 in culture, and inhibited tumor growth in cell line xenograft models (PMID: 27136102).||27136102|
|FGFR2 positive||ovarian cancer||predicted - sensitive||Alofanib||Preclinical - Cell culture||Actionable||In a preclinical study, Alofanib (RPT835) inhibited growth in an ovarian cancer cell line expressing FGFR2 in culture (PMID: 27136102).||27136102|