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Biophysical characterization of drug‐resistant mutants of fibroblast growth factor receptor 1
Author(s) -
Yoza Kaito,
Himeno Rika,
Amano Shinjiro,
Kobashigawa Yoshihiro,
Amemiya Shun,
Fukuda Natsuki,
Kumeta Hiroyuki,
Morioka Hiroshi,
Inagaki Fuyuhiko
Publication year - 2016
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/gtc.12405
Subject(s) - biology , ponatinib , tyrosine kinase , mutant , receptor tyrosine kinase , kinase , fibroblast growth factor receptor 1 , tyrosine , tyrosine kinase inhibitor , biochemistry , mutation , receptor , fibroblast growth factor , genetics , cancer , gene , dasatinib
Over‐expression and aberrant activation of tyrosine kinases occur frequently in human cancers. Various tyrosine kinase inhibitors ( TKI s) are under clinical use, but acquisition of resistance to these drugs is a major problem. Here, we studied the interaction between two drug‐resistant mutants of fibroblast growth factor receptor 1 ( FGFR 1), N546K and V561M, and four ATP ‐competitive inhibitors, ponatinib, dovitinib, PD 173074 and BGJ ‐398. Among these protein–drug systems, the only marked reduction in affinity was that of PD 173074 for the V561M mutant. We also examined the interaction of these FGFR 1 variants to AMP ‐ PNP , a nonhydrolyzable analogue of ATP , and showed that N546K showed increased affinity for the ATP analogue as compared with the wild type. These findings will help to clarify the mechanism of drug resistance in mutant tyrosine kinases.