The N550K/H mutations in FGFR2 confer differential resistance to PD173074, dovitinib and ponatinib ATP-competitive inhibitors


Autoria(s): Byron, Sara A.; Chen, Huaibin; Wortmann, Andreas; Loch, David; Gartside, Michael; Dehkhoda, Farhad; Blais, Steven P.; Neubert, Thomas A.; Mohammadi, Moosa; Pollock, Pamela M.
Data(s)

01/05/2013

Resumo

We sought to identify fibroblast growth factor receptor 2 (FGFR2) kinase domain mutations that confer resistance to the pan-FGFR inhibitor, dovitinib, and explore the mechanism of action of the drug-resistant mutations. We cultured BaF3 cells overexpressing FGFR2 in high concentrations of dovitinib and identified fourteen dovitinib-resistant mutations, including the N550K mutation observed in 25% of FGFR2mutant endometrial cancers (EC). Structural and biochemical in vitro kinase analyses, together with BaF3 proliferation assays, showed that the resistance mutations elevate the intrinsic kinase activity of FGFR2. BaF3 lines were used to assess the ability of each mutation to confer cross-resistance to PD173074 and ponatinib. Unlike PD173074, ponatinib effectively inhibited all the dovitinib-resistant FGFR2 mutants except the V565I gatekeeper mutation, suggesting ponatinib but not dovitinib targets the active conformation of FGFR2 kinase. EC cell lines expressing wild-type FGFR2 were relatively resistant to all inhibitors. Whereas EC cell lines expressing mutated FGFR2 showed differential sensitivity. Within the FGFR2mutant cell lines, 3/7 showed marked resistance to PD173074 and relative resistance to dovitinib and ponatinib. This suggests that alternative mechanisms distinct from kinase domain mutations are responsible for intrinsic resistance in these three EC lines. Finally, overexpression of FGFR2N550K in JHUEM-2 cells (FGFR2C383R) conferred resistance (~5 fold) to PD173074, providing independent data that FGFR2N550K can be associated with drug resistance. Biochemical in vitro kinase analyses also shows ponatinib is more effective than dovitinib at inhibiting FGFR2N550K. We propose tumors harboring mutationally activated FGFRs should be treated with FGFR inhibitors that specifically bind the active kinase.

Formato

application/pdf

Identificador

http://eprints.qut.edu.au/60164/

Publicador

Neoplasia Press, Inc

Relação

http://eprints.qut.edu.au/60164/1/NeoplasiaRevised_12-1106.pdf

DOI:10.1593/neo.121106

Byron, Sara A., Chen, Huaibin, Wortmann, Andreas, Loch, David, Gartside, Michael, Dehkhoda, Farhad, Blais, Steven P. , Neubert, Thomas A. , Mohammadi, Moosa, & Pollock, Pamela M. (2013) The N550K/H mutations in FGFR2 confer differential resistance to PD173074, dovitinib and ponatinib ATP-competitive inhibitors. NeoPlasia, 15(8), pp. 975-988.

Direitos

Copyright 2013 Neoplasia Press, Inc

Fonte

School of Biomedical Sciences; Faculty of Health; Institute of Health and Biomedical Innovation

Palavras-Chave #060100 BIOCHEMISTRY AND CELL BIOLOGY #060400 GENETICS #111200 ONCOLOGY AND CARCINOGENESIS #FGFR #dovitinib #ponatinib #resistance #mutation #PD173074 #inhibition #gatekeeper
Tipo

Journal Article