Crenolanib Inhibits the Drug-Resistant PDGFRA D842V Mutation Associated with Imatinib-resistant Gastrointestinal Stromal Tumors
Menée sur des lignées cellulaires de tumeurs stromales gastro-intestinales, cette étude évalue l'intérêt du crenolanib pour le traitement de tumeurs résistantes à l'imatinib et présentant une mutation de PDGFRA
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 crenolanib was compared to imatinib using a panel of PDGFRA mutant kinases expressed in several different cell line models, including primary GIST cells. The anti-proliferative activity of crenolanib was also studied in several cell lines with PDGFRA-dependent growth. Results: Crenolanib was significantly more potent than imatinib in inhibiting the kinase activity of imatinib-resistant PDGFRA kinases (D842I, D842V, D842Y, DI842-843IM, and deletion I843). For example, crenolanib was 135-fold more potent than imatinib against D842V in our isogenic model system, with an IC50 of approximately 10 nM The relative potency of crenolanib was further confirmed in BaF3 and primary GIST cells expressing PDGFRA D842V. In contrast, imatinib was at least 10-fold more potent than crenolanib in inhibiting the V561D mutation. For all other tested PDGFRA mutations, crenolanib and imatinib had comparable potency. Conclusions: Crenolanib is a potent inhibitor of imatinib-resistant PDGFRA kinases associated with GIST, including the PDGFRA D842V mutation found in ~5% of GISTs. The spectrum of activity of crenolanib suggests 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 GIST with the PDGFRA D842V mutation has been initiated (NCT01243346).