Cumulative mechanism of several major imatinib-resistant mutations in Abl kinase.
Proc Natl Acad Sci U S A
; 117(32): 19221-19227, 2020 08 11.
Article
de En
| MEDLINE
| ID: mdl-32719139
ABSTRACT
Despite the outstanding success of the cancer drug imatinib, one obstacle in prolonged treatment is the emergence of resistance mutations within the kinase domain of its target, Abl. We noticed that many patient-resistance mutations occur in the dynamic hot spots recently identified to be responsible for imatinib's high selectivity toward Abl. In this study, we provide an experimental analysis of the mechanism underlying drug resistance for three major resistance mutations (G250E, Y253F, and F317L). Our data settle controversies, revealing unexpected resistance mechanisms. The mutations alter the energy landscape of Abl in complex ways increased kinase activity, altered affinity, and cooperativity for the substrates, and, surprisingly, only a modestly decreased imatinib affinity. Only under cellular adenosine triphosphate (ATP) concentrations, these changes cumulate in an order of magnitude increase in imatinib's half-maximal inhibitory concentration (IC50). These results highlight the importance of characterizing energy landscapes of targets and its changes by drug binding and by resistance mutations developed by patients.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Protéines oncogènes v-abl
/
Mésilate d'imatinib
/
Tumeurs
/
Antinéoplasiques
Limites:
Humans
Langue:
En
Journal:
Proc Natl Acad Sci U S A
Année:
2020
Type de document:
Article