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

0483011 - ÚŽFG 2018 RIV US eng J - Článek v odborném periodiku
Bálek, L. - Gudernová, I. - Veselá, Iva - Hampl, Marek - Oralová, Veronika - Kunová Bosáková, M. - Vařecha, M. - Němec, P. - Hall, T.C. - Abbadessa, G. - Hatch, N. - Buchtová, Marcela - Krejčí, P.
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.
Bone. Roč. 105, č. 1 (2017), s. 57-66. ISSN 8756-3282. E-ISSN 1873-2763
Grant CEP: GA ČR(CZ) GA17-09525S; GA ČR(CZ) GA14-31540S
Institucionální podpora: RVO:67985904
Klíčová slova: ARQ087 * fibroblast growth factor receptor * FGFR
Obor OECD: Developmental biology
Impakt faktor: 4.455, rok: 2017

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.
Trvalý link: http://hdl.handle.net/11104/0278435