ATP-competitive inhibitors midostaurin and avapritinib have distinct resistance profiles in exon 17–mutant kit

Abstract

KIT is a type-3 receptor tyrosine kinase that is frequently domain substitutions, with the T670I gatekeeper mutation mutated at exon 11 or 17 in a variety of cancers. First-being selectively problematic for avapritinib. Although generation KIT tyrosine kinase inhibitors (TKI) are ineffec-gatekeeper mutations often directly disrupt inhibitor bind-tive against KIT exon 17 mutations, which favor an active ing, we provide evidence that T670I confers avapritinib conformation that prevents these TKIs from binding. resistance indirectly by inducing distant conformational The ATP-competitive inhibitors, midostaurin and avapriti-changes in the phosphate-binding loop. These findings nib, which target the active kinase conformation, were suggest combining midostaurin and avapritinib may fore-developed to inhibit exon 17–mutant KIT. Because second-stall acquired resistance mediated by secondary kinase ary kinase domain mutations are a common mechanism domain mutations. of TKI resistance and guide ensuing TKI design, we sought to define problematic KIT kinase domain mutations for Significance: This study identifies potential problematic these emerging therapeutics. Midostaurin and avapritinib kinase domain mutations for next-generation KIT inhibitors displayed different vulnerabilities to secondary kinase midostaurin and avapritinib.