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

Authors
 Turcin Saridogan  ;  Argun Akcakanat  ;  Ming Zhao  ;  Kurt W Evans  ;  Erkan Yuca  ;  Stephen Scott  ;  Bryce P Kirby  ;  Xiaofeng Zheng  ;  Min Jin Ha  ;  Huiqin Chen  ;  Patrick K S Ng  ;  Timothy P DiPeri  ;  Gordon B Mills  ;  Jordi Rodon Ahnert  ;  Senthil Damodaran  ;  Funda Meric-Bernstam 
Citation
 SCIENTIFIC REPORTS, Vol.13(1) : 20223, 2023-11 
Journal Title
SCIENTIFIC REPORTS
Issue Date
2023-11
MeSH
Animals ; Breast Neoplasms* / drug therapy ; Breast Neoplasms* / genetics ; Breast Neoplasms* / metabolism ; Disease Models, Animal ; Female ; Humans ; Pyrazoles ; Pyrimidines / pharmacology ; Pyrroles ; Receptor, Fibroblast Growth Factor, Type 1 / genetics ; Receptor, Fibroblast Growth Factor, Type 2 / metabolism ; Receptors, Fibroblast Growth Factor / metabolism
Abstract
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.
Files in This Item:
T992023052.pdf Download
DOI
10.1038/s41598-023-46586-y
Appears in Collections:
4. Graduate School of Public Health (보건대학원) > Graduate School of Public Health (보건대학원) > 1. Journal Papers
Yonsei Authors
Ha, Min Jin(하민진)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/199317
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