| RRC ID |
44564
|
| 著者 |
Byron SA, Chen H, Wortmann A, Loch D, Gartside MG, Dehkhoda F, Blais SP, Neubert TA, Mohammadi M, Pollock PM.
|
| タイトル |
The N550K/H mutations in FGFR2 confer differential resistance to PD173074, dovitinib, and ponatinib ATP-competitive inhibitors.
|
| ジャーナル |
Neoplasia
|
| Abstract |
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 14 dovitinib-resistant mutations, including the N550K mutation observed in 25% of FGFR2(mutant) endometrial cancers (ECs). 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 FGFR2(mutant) cell lines, three of seven 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 FGFR2(N550K) in JHUEM-2 cells (FGFR2(C383R)) conferred resistance (about five-fold) to PD173074, providing independent data that FGFR2(N550K) can be associated with drug resistance. Biochemical in vitro kinase analyses also show that ponatinib is more effective than dovitinib at inhibiting FGFR2(N550K). We propose that tumors harboring mutationally activated FGFRs should be treated with FGFR inhibitors that specifically bind the active kinase.
|
| 巻・号 |
15(8)
|
| ページ |
975-88
|
| 公開日 |
2013-8-1
|
| DOI |
10.1593/neo.121106
|
| PMID |
23908597
|
| PMC |
PMC3730048
|
| MeSH |
Adenosine Triphosphate / metabolism
Animals
Benzimidazoles / pharmacology*
Binding Sites / genetics
Biocatalysis / drug effects
Cell Line
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Resistance, Neoplasm / drug effects
Drug Resistance, Neoplasm / genetics
Electrophoresis, Polyacrylamide Gel
Endometrial Neoplasms / genetics
Endometrial Neoplasms / metabolism
Endometrial Neoplasms / pathology
Female
Humans
Imidazoles / pharmacology*
Inhibitory Concentration 50
Models, Molecular
Mutation*
Phosphorylation / drug effects
Protein Kinase Inhibitors / pharmacology
Protein Structure, Tertiary
Pyridazines / pharmacology*
Pyrimidines / pharmacology*
Quinolones / pharmacology*
Receptor, Fibroblast Growth Factor, Type 2 / chemistry
Receptor, Fibroblast Growth Factor, Type 2 / genetics*
Receptor, Fibroblast Growth Factor, Type 2 / metabolism
|
| IF |
5.696
|
| 引用数 |
67
|
|
WOS 分野
|
ONCOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
JHUEM-2(RCB1551) |
