Combinatorial Targeting of Avapritinib-Driven MAP Kinase Activation in High-Grade Glioma

PDGFRA alterations define a high-risk subset of high-grade glioma (HGG), yet targeted therapies have yielded limited and transient benefit. Here, we show that the CNS-penetrant PDGFRA inhibitor avapritinib induces sustained MAPK pathway activation at supratherapeutic dosing, revealing a therapy-induced adaptive vulnerability. High-dimensional kinome profiling (>900 nodes) and in vivo studies demonstrate robust, dose-dependent ERK activation following avapritinib treatment. This response is enriched in cycling oligodendrocyte precursor cell-like (OPC-like) tumor populations and promotes survival through ERK-dependent stabilization of the anti-apoptotic protein MCL-1. Modeling of clinically relevant PDGFRA variants reveals that D842V-mutant tumor cells exhibit heightened MAPK activation and potential for MAPK co-targeting. Rational combination strategies suppress this adaptive signaling, with MEK inhibition producing durable pathway suppression and significant survival benefit in vivo. Translation to patients demonstrates feasibility and early clinical activity, including a sustained complete regression in an unresected PDGFRA-mutant HGG treated with avapritinib and the MEK1/2 inhibitor selumetinib. Together, these findings identify adaptive MAPK reactivation as a targetable liability and support combined PDGFRA–MAPK inhibition as a therapeutic strategy.