Efficacy of futibatinib, an irreversible fibroblast growth factor receptor inhibitor, in FGFR-altered breast cancer

• Published in: Scientific reports Vol. 13; no. 1; pp. 20223 - 15
• Main Authors: Saridogan, Turcin, Akcakanat, Argun, Zhao, Ming, Evans, Kurt W., Yuca, Erkan, Scott, Stephen, Kirby, Bryce P., Zheng, Xiaofeng, Ha, Min Jin, Chen, Huiqin, Ng, Patrick K. S., DiPeri, Timothy P., Mills, Gordon B., Rodon Ahnert, Jordi, Damodaran, Senthil, Meric-Bernstam, Funda
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.11.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 631/208/69; 692/4028/67/1059; 692/4028/67/1347; Animals; Antitumor activity; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Disease Models, Animal; Female; Fibroblast growth factor receptor 1; Fibroblast growth factor receptor 2; Fibroblast growth factor receptors; Fibroblasts; Gene expression; Growth factors; Humanities and Social Sciences; Humans; multidisciplinary; Pyrazoles; Pyrimidines - pharmacology; Pyrroles; Receptor, Fibroblast Growth Factor, Type 1 - genetics; Receptor, Fibroblast Growth Factor, Type 2 - metabolism; Receptors, Fibroblast Growth Factor - metabolism; Science; Science (multidisciplinary); Therapeutic targets; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-023-46586-y

Several alterations in fibroblast growth factor receptor (FGFR) genes have been found in breast cancer; however, they have not been well characterized as therapeutic targets. Futibatinib (TAS-120; Taiho) is a novel, selective, pan-FGFR inhibitor that inhibits FGFR1-4 at nanomolar concentrations. We sought to determine futibatinib’s efficacy in breast cancer models. Nine breast cancer patient–derived xenografts (PDXs) with various FGFR1-4 alterations and expression levels were treated with futibatinib. Antitumor efficacy was evaluated by change in tumor volume and time to tumor doubling. Alterations indicating sensitization to futibatinib in vivo were further characterized in vitro . FGFR gene expression between patient tumors and matching PDXs was significantly correlated; however, overall PDXs had higher FGFR3-4 expression. Futibatinib inhibited tumor growth in 3 of 9 PDXs, with tumor stabilization in an FGFR2 -amplified model and prolonged regression (> 110 days) in an FGFR2 Y375C mutant/amplified model. FGFR2 overexpression and, to a greater extent, FGFR2 Y375C expression in MCF10A cells enhanced cell growth and sensitivity to futibatinib. Per institutional and public databases, FGFR2 mutations and amplifications had a population frequency of 1.1%–2.6% and 1.5%–2.5%, respectively, in breast cancer patients. FGFR2 alterations in breast cancer may represent infrequent but highly promising targets for futibatinib.