Co-targeting CDK4/6 and MEK reverses mesenchymal transition in therapy-refractory BRAF-altered pediatric high-grade glioma.
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BACKGROUND: BRAF-altered pediatric high-grade gliomas (pHGG) harbor a dismal prognosis. Although targeted therapy with BRAF and MEK inhibitors provides initial benefit, resistance emerges rapidly in clinical practice indicating an urgent need for improved therapeutic strategies. As BRAF mutations frequently co-occur with homozygous CDKN2A/B loss, we investigated CDK4/6 inhibition as a rational therapeutic strategy. METHODS: Using BRAF-mutant cell and human-to-organoid transplant (HOT) models, we assessed the impact of CDK4/6 and MEK inhibitors as mono- or combination therapies on viability, apoptosis, senescence, and molecular signaling. Activation of signaling pathways in primary and recurrent matched samples pre- and post-combined MEK and BRAF treatment was examined by RNA sequencing. In vivo efficacy was evaluated in orthotopic and subcutaneous patient-derived xenograft (PDX) models, as well as in one clinical case. RESULTS: BRAF-mutant, CDKN2A/B-deficient pHGGs displayed strong sensitivity to the CDK4/6 inhibitor abemaciclib in addition to the MEK inhibitor trametinib. These tumors were particularly vulnerable to combined abemaciclib and trametinib treatment, which induced senescence and apoptosis, and uniquely suppressed mTOR activity. Both HOT and PDX models exhibited tumor regression, prolonged survival and sustained response even after therapy discontinuation. These effects were accompanied by a decreased mesenchymal-like cellular phenotype, as indicated by lower CD44 expression and a shift toward a more rounded cell morphology. Interestingly, trametinib- and dabrafenib post-treatment samples exhibited further increase in CD44 levels, along with upregulation of PI3K and hypoxia signaling, indicating therapy-associated reinforcement of mesenchymal transition. The combination of trametinib and ribociclib was translated into clinical application, by showing good response of a patient with BRAF-altered and therapy-refractory pHGG. CONCLUSION: Our study demonstrated enhanced and prolonged effects of combined CDK4/6 and MEK inhibition in BRAF/CDKN2A-co-altered recurrent pHGG. We further provide evidence that the aggressive mesenchymal cell compartment is particularly targeted by this treatment combination, warranting further preclinical and clinical investigation.