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

J 2017

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

BÁLEK, Lukáš; Iva GUDERNOVÁ; Iva VESELA; Marek HAMPL; Veronika ORALOVÁ et. al.

Základní údaje

Originální název

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

Autoři

Vydání

Bone, NEW YORK, Elsevier, 2017, 8756-3282

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30202 Endocrinology and metabolism

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Impakt faktor

Impact factor: 4.455

Kód RIV

RIV/00216224:14110/17:00095264

Organizační jednotka

Lékařská fakulta

DOI

https://doi.org/10.1016/j.bone.2017.08.016

UT WoS

000413994500008

EID Scopus

2-s2.0-85028050791

Klíčová slova anglicky

ARQ 087; Fibroblast growth factor receptor; FGFR; Skeletal dysplasia; Achondroplasia; Craniosynostosis; Inhibitor

Štítky

EL OK, podil

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 5. 12. 2018 12:47, Soňa Böhmová

Anotace

V originále

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.

Návaznosti

GA17-09525S, projekt VaV

Název: Neobvyklé signální dráhy lidských receptorových tyrozinových kináz

Investor: Grantová agentura ČR, Neobvyklé signální dráhy lidských receptorových tyrozinových kináz

LQ1601, projekt VaV

Název: CEITEC 2020 (Akronym: CEITEC2020)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, CEITEC 2020

NV15-33232A, projekt VaV

Název: Identifikace nových možností léčby achondroplásie prostřednictvím analýzy interakce FGFR3 a adaptérového proteinu Frs2

NV15-34405A, projekt VaV

Název: Identifikace nových možností léčby chronické myeloidní leukémie pomocí systematické analýzy interaktomu proteinu BCR-ABL

ROZV/25/LF/2017, interní kód MU

Název: LF - Příspěvek na IP 2017

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, LF - Příspěvek na IP 2017, Interní rozvojové projekty

Citovat

BÁLEK, Lukáš; Iva GUDERNOVÁ; Iva VESELA; Marek HAMPL; Veronika ORALOVÁ; Michaela BOSÁKOVÁ; Miroslav VAŘECHA; Pavel NĚMEC; Terence HALL; Giovanni ABBADESSA; Nan HATCH; marcela BUCHTOVÁ a Pavel KREJČÍ. 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. NEW YORK: Elsevier, 2017, roč. 105, DEC 2017, s. 57-66. ISSN 8756-3282. Dostupné z: https://doi.org/10.1016/j.bone.2017.08.016.

@article{1399055,
   author = {Bálek, Lukáš and Gudernová, Iva and Vesela, Iva and Hampl, Marek and Oralová, Veronika and Bosáková, Michaela and Vařecha, Miroslav and Němec, Pavel and Hall, Terence and Abbadessa, Giovanni and Hatch, Nan and Buchtová, marcela and Krejčí, Pavel},
   article_location = {NEW YORK},
   article_number = {DEC 2017},
   doi = {https://doi.org/10.1016/j.bone.2017.08.016},
   keywords = {ARQ 087; Fibroblast growth factor receptor; FGFR; Skeletal dysplasia; Achondroplasia; Craniosynostosis; Inhibitor},
   language = {eng},
   issn = {8756-3282},
   journal = {Bone},
   title = {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},
   volume = {105},
   year = {2017}
}

TY  - JOUR
ID  - 1399055
AU  - 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
PY  - 2017
TI  - 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
JF  - Bone
VL  - 105
IS  - DEC 2017
SP  - 57-66
EP  - 57-66
PB  - Elsevier
SN  - 87563282
KW  - ARQ 087
KW  - Fibroblast growth factor receptor
KW  - FGFR
KW  - Skeletal dysplasia
KW  - Achondroplasia
KW  - Craniosynostosis
KW  - Inhibitor
N2  - 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.
ER  -

BÁLEK, Lukáš; Iva GUDERNOVÁ; Iva VESELA; Marek HAMPL; Veronika ORALOVÁ; Michaela BOSÁKOVÁ; Miroslav VAŘECHA; Pavel NĚMEC; Terence HALL; Giovanni ABBADESSA; Nan HATCH; marcela BUCHTOVÁ a Pavel KREJČÍ. 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. \textit{Bone}. NEW YORK: Elsevier, 2017, roč.~105, DEC 2017, s.~57-66. ISSN~8756-3282. Dostupné z: https://doi.org/10.1016/j.bone.2017.08.016.

Přehled o publikaci