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.

Basic information

Original name

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 (203 Czech Republic, belonging to the institution), Iva GUDERNOVÁ (203 Czech Republic, belonging to the institution), Iva VESELA (203 Czech Republic), Marek HAMPL (203 Czech Republic, belonging to the institution), Veronika ORALOVÁ (203 Czech Republic), Michaela BOSÁKOVÁ (203 Czech Republic, belonging to the institution), Miroslav VAŘECHA (203 Czech Republic, belonging to the institution), Pavel NĚMEC (203 Czech Republic, belonging to the institution), Terence HALL (840 United States of America), Giovanni ABBADESSA (840 United States of America), Nan HATCH (840 United States of America), marcela BUCHTOVÁ (203 Czech Republic, belonging to the institution) and Pavel KREJČÍ (203 Czech Republic, guarantor, belonging to the institution)

Edition

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

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30202 Endocrinology and metabolism

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

Impact factor

Impact factor: 4.455

RIV identification code

RIV/00216224:14110/17:00095264

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1016/j.bone.2017.08.016

UT WoS

000413994500008

Keywords in English

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

Abstract

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.

Links

GA17-09525S, research and development project

Name: Neobvyklé signální dráhy lidských receptorových tyrozinových kináz

Investor: Czech Science Foundation

LQ1601, research and development project

Name: CEITEC 2020 (Acronym: CEITEC2020)

Investor: Ministry of Education, Youth and Sports of the CR

NV15-33232A, research and development project

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

NV15-34405A, research and development project

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

ROZV/25/LF/2017, interní kód MU

Name: LF - Příspěvek na IP 2017

Investor: Ministry of Education, Youth and Sports of the CR, Internal development projects

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 and 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, vol. 105, DEC 2017, p. 57-66. ISSN 8756-3282. Available from: https://dx.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 = {http://dx.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 and 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, vol.~105, DEC 2017, p.~57-66. ISSN~8756-3282. Available from: https://dx.doi.org/10.1016/j.bone.2017.08.016.

Detailed Information on Publication Record