Crenolanib Inhibits the Drug-Resistant PDGFRA D842V Mutation Associated with Imatinib-Resistant Gastrointestinal Stromal Tumors

Abstract Purpose: To determine the potential of crenolanib, a potent inhibitor of PDGFRA, to treat malignancies driven by mutant PDGFRA. Experimental Design: The biochemical activity of crenolanibwas compared to imatinibusing a panel of PDGFRAmutant kinases expressed in several different cell line models, including primary GISTcells. The anti-proliferative activity of crenolanibwas also studied in several cell lines with PDGFRA-dependent growth. Results: Crenolanibwas significantly more potent than imatinibin inhibiting the kinase activity of imatinib-resistant PDGFRAkinases (D842I, D842V, D842Y, DI842-843IM, and deletion I843). For example, crenolanibwas 135-fold more potent than imatinibagainst D842V in our isogenic model system, with an IC50 of approximately 10 nM The relative potency of crenolanibwas further confirmed in BaF3 and primary GISTcells expressing PDGFRAD842V. In contrast, imatinibwas at least 10-fold more potent than crenolanibin inhibiting the V561D mutation. For all other tested PDGFRAmutations, crenolaniband imatinibhad comparable potency. Conclusions: Crenolanibis a potent inhibitor of imatinib-resistant PDGFRAkinases associated with GIST, including the PDGFRAD842V mutation found in ~5% of GISTs. The spectrum of activity of crenolanibsuggests that this drug is a type I inhibitor (inhibitor of activated conformation of kinase). Based in part on these results, a phase 2 clinical study of this agent to treat GISTwith the PDGFRAD842V mutation has been initiated (NCT01243346).