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Cancer Res. 2019 Aug 15;79(16):4283-4292. doi: 10.1158/0008-5472.CAN-18-3139. Epub 2019 Jul 3.

ATP-Competitive Inhibitors Midostaurin and Avapritinib Have Distinct Resistance Profiles in Exon 17-Mutant KIT.

Author information

1
Division of Hematology/Oncology, Department of Pediatrics, University of California San Francisco, San Francisco, California.
2
Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California.
3
Department of Medicine, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California.
4
Beijing Key Laboratory of Environmental & Viral Oncology, College of Life Science and Bioengineering, Beijing University of Technology, Beijing, China.
5
Department of Dermatology, University of California San Francisco, San Francisco, California.
6
Department of Medicine, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California. neil.shah@ucsf.edu.

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.

PMID:
31270078
PMCID:
PMC6697585
[Available on 2020-02-15]
DOI:
10.1158/0008-5472.CAN-18-3139

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