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ATP-Competitive Inhibitors Midostaurin and Avapritinib Have Distinct Resistance Profiles in Exon 17-Mutant KIT.
- Source :
-
Cancer research [Cancer Res] 2019 Aug 15; Vol. 79 (16), pp. 4283-4292. Date of Electronic Publication: 2019 Jul 03. - Publication Year :
- 2019
-
Abstract
- KIT is a type-3 receptor tyrosine kinase that is frequently mutated at exon 11 or 17 in a variety of cancers. First-generation KIT tyrosine kinase inhibitors (TKI) are ineffective against KIT exon 17 mutations, which favor an active conformation that prevents these TKIs from binding. The ATP-competitive inhibitors, midostaurin and avapritinib, which target the active kinase conformation, were developed to inhibit exon 17-mutant KIT. Because secondary kinase domain mutations are a common mechanism of TKI resistance and guide ensuing TKI design, we sought to define problematic KIT kinase domain mutations for these emerging therapeutics. Midostaurin and avapritinib displayed different vulnerabilities to secondary kinase domain substitutions, with the T670I gatekeeper mutation being selectively problematic for avapritinib. Although gatekeeper mutations often directly disrupt inhibitor binding, we provide evidence that T670I confers avapritinib resistance indirectly by inducing distant conformational changes in the phosphate-binding loop. These findings suggest combining midostaurin and avapritinib may forestall acquired resistance mediated by secondary kinase domain mutations. SIGNIFICANCE: This study identifies potential problematic kinase domain mutations for next-generation KIT inhibitors midostaurin and avapritinib.<br /> (©2019 American Association for Cancer Research.)
- Subjects :
- Cell Line
Drug Resistance, Neoplasm drug effects
Exons
Humans
Molecular Docking Simulation
Molecular Dynamics Simulation
Mutation
Proto-Oncogene Proteins c-kit chemistry
Proto-Oncogene Proteins c-kit metabolism
Staurosporine chemistry
Staurosporine pharmacology
Antineoplastic Agents pharmacology
Drug Resistance, Neoplasm genetics
Protein Kinase Inhibitors pharmacology
Proto-Oncogene Proteins c-kit genetics
Pyrazoles pharmacology
Pyrroles pharmacology
Staurosporine analogs & derivatives
Triazines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 79
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 31270078
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-18-3139