Document Type
Article
Publication Date
11-18-2023
Original Citation
Saridogan T,
Akcakanat A,
Zhao M,
Evans K,
Yuca E,
Scott S,
Kirby B,
Zheng X,
Ha M,
Chen H,
Ng P,
DiPeri T,
Mills G,
Rodon Ahnert J,
Damodaran S,
Meric-Bernstam F.
Efficacy of futibatinib, an irreversible fibroblast growth factor receptor inhibitor, in FGFR-altered breast cancer. Sci Rep. 2023;13(1):20223. Epub 20231118.
Keywords
JGM, Animals, Humans, Female, Breast Neoplasms, Receptors, Fibroblast Growth Factor, Receptor, Fibroblast Growth Factor, Type 2, Pyrazoles, Pyrimidines, Pyrroles, Receptor, Fibroblast Growth Factor, Type 1, Disease Models, Animal
JAX Source
Sci Rep. 2023;13(1):20223. Epub 20231118.
ISSN
2045-2322
PMID
37980453
DOI
https://doi.org/10.1038/s41598-023-46586-y
Grant
This work was supported by grants from Taiho Pharmaceuticals, The National Cancer Institute PDX Development and Trial Center (U54 #CA224065), The Nellie B. Connally Breast Cancer Research Endowment, The University of Texas MD Anderson Cancer Center Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer, The University of Texas MD Anderson Breast Cancer Moonshot Program, a NIH Clinical Translational Sci- ence Award (1UL1TR003167), and The University of Texas MD Anderson Cancer Center Support Grant (P30 CA016672) and UO1 CA217842-06 (FM-B), Breast Cancer Research Foundation (BCRF-21–110), and Susan G. Komen Foundation (SAC110052) (GBM).
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.
Comments
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