Resistance to Avapritinib in PDGFRA-Driven GIST Is Caused by Secondary Mutations in the PDGFRA Kinase Domain

Abstract Gastrointestinal stromal tumors (GIST) harboring activating mutations of PDGFRA respond to imatinib, with the notable exception most common mutation, D842V. Avapritinib is a novel, potent KIT/PDGFRA inhibitor substantial clinical activity in patients D842V genotype. To date, only minority PDGFRA-mutant treated avapritinib have developed secondary resistance. Tumor and plasma biopsies 6 7 primary who progressed on or imatinib had resistance within exons 13, 14, 15 that interfere binding. Secondary causing V658A, N659K, Y676C, G680R substitutions were found 2 more each, representing recurrent mechanisms GIST drug Notably, GISTs refractory remain dependent oncogenic signal. Inhibitors target protein stability inhibition PDGFRA-dependent signaling pathways may overcome Significance: Here, we provide first description GIST. This article highlighted In Issue feature, p. 1