DNAR-07. BET PROTEIN INHIBITION SENSITIZES GLIOBLASTOMA CELLS TO TEMOZOLOMIDE TREATMENT BY ATTENUATING MGMT EXPRESSION

Abstract Bromodomain and extra-terminal tail (BET) proteins have been identified as potential epigenetic targets in cancer, including glioblastoma. These modifiers link the histone code to gene transcription that can be disrupted with small molecule BET inhibitors (BETi). With aim of identifying rational combination treatments for glioblastoma, we analyzed BETi-induced differential expression glioblastoma derived-spheres. This 6 distinct patterns. To uncover emerging actionable vulnerabilities targeted a second drug, extracted significantly disturbed DNA Damage Response genes. Among constantly downregulated candidates was O-6-methylguanine-DNA methyltransferase (MGMT) gene, known resistance factor alkylating agent therapy BETi not only reduced MGMT GBM cell lines, but also inhibited its induction, typically observed upon temozolomide treatment. determine clinical relevance, evaluated specificity effect on mediated treatment temozolomide. BETi-mediated attenuation associated reduction BRD4- Pol II-binding at promoter. On functional level, demonstrated ectopic under an unrelated promoter affected by BETi, while same conditions, pharmacologic inhibition restored sensitivity temozolomide, reflected increased level gammaH2AX. Importantly, members mismatch repair pathway, required unrepaired O6G-lesions, namely MSH6 MSH2, were transiently BETi. Taken together, addition BET-inhibitors current standard care, comprising treatment, may improve outcome 50% patients whose exert unmethylated