Disrupting MED8-dependent epigenetic reprogramming augments avapritinib sensitivity in PDGFRA-driven glioma.

PDGFRA genetic alterations are a well-established oncogenic driver in gliomas. However, targeted monotherapy against PDGFRA such as avapritinib has achieved limited clinical efficacy, and the mechanism underlying avapritinib resistance remains poorly understood. Multi-omics analysis of clinical samples identified super-enhancer (SE) complex components. Comprehensive preclinical evaluation was performed using glioma cell lines, glioma stem cells, patient-derived cells, xenografts, and organoids. Mechanistic investigations integrated Cleavage Under Targets and Tagmentation, chromatin immunoprecipitation, co-immunoprecipitation, mass spectrometry, protein fragment complementation, and dual-luciferase reporter assays. Functional and clinical analyses identified the SE complex component MED8 as significantly upregulated in gliomas and correlated with poor prognosis. MED8 was essential for tumor proliferation and survival both in vitro and in vivo. Mechanistically, MED8 cooperated with CDK7 to bind and activate the SEs of PDGFRA, sustaining high transcriptional output of this oncogene. We repurposed FDA-approved venetoclax as a first-in-class MED8-targeting agent that potently sensitizes to avapritinib, exerting synergistic effects in multiple preclinical models. This study delineates a novel MED8-SE-PDGFRA epigenetic axis driving resistance. The combination of avapritinib and venetoclax, co-targeting the oncogenic signal and its transcriptional regulator, presents a translatable dual-targeting strategy to improve outcomes in PDGFRA-driven glioma.