Publication details

ARQ 087 inhibits FGFR signaling and rescues aberrant cell proliferation and differentiation in experimental models of craniosynostoses and chondrodysplasias caused by activating mutations in FGFR1, FGFR2 and FGFR3

Authors

BÁLEK Lukáš GUDERNOVÁ Iva VESELA Iva HAMPL Marek ORALOVÁ Veronika BOSÁKOVÁ Michaela VAŘECHA Miroslav NĚMEC Pavel HALL Terence ABBADESSA Giovanni HATCH Nan BUCHTOVÁ marcela KREJČÍ Pavel

Year of publication 2017
Type Article in Periodical
Magazine / Source Bone
MU Faculty or unit

Faculty of Medicine

Citation
Doi http://dx.doi.org/10.1016/j.bone.2017.08.016
Field Endocrinology, diabetology, metabolism, nutrition
Keywords ARQ 087; Fibroblast growth factor receptor; FGFR; Skeletal dysplasia; Achondroplasia; Craniosynostosis; Inhibitor
Description Tyrosine kinase inhibitors are being developed for therapy of malignancies caused by oncogenic FGFR signaling but little is known about their effect in congenital chondrodysplasias or craniosynostoses that associate with activating FGFR mutations. Here, we investigated the effects of novel FGFR inhibitor, ARQ 087, in experimental models of aberrant FGFR3 signaling in cartilage. In cultured chondrocytes, ARQ 087 efficiently rescued all major effects of pathological FGFR3 activation, i.e. inhibition of chondrocyte proliferation, loss of extracellular matrix and induction of premature senescence. In ex vivo tibia organ cultures, ARQ087 restored normal growth plate architecture and eliminated the suppressing FGFR3 effect on chondrocyte hypertrophic differentiation, suggesting that it targets the FGFR3 pathway specifically, i.e. without interference with other pro-growth pathways. Moreover, ARQ 087 inhibited activity of FGFR1 and FGFR2 mutants associated with Pfeiffer, Apert and Beare-Stevenson craniosynostoses, and rescued FGFR-driven excessive osteogenic differentiation in mouse mesenchymal micromass cultures or in ex vivo calvarial organ cultures. Our data warrant further development of ARQ 087 for clinical use in skeletal disorders caused by activating FGFR mutations. (C) 2017 Elsevier Inc. All rights reserved.
Related projects:

You are running an old browser version. We recommend updating your browser to its latest version.

More info