CNSC-10. CDK7 INHIBITION MITIGATES AZD1775 RESISTANCE VIA CHROMATIN REPROGRAMMING IN MYC-MB

Abstract Medulloblastoma (MB) is the most common malignant brain tumor in children, comprising ~20% of pediatric brain tumors. MB is a heterogeneous disease, with clinical outcomes heavily influenced by molecular subgroups. Among these, Group 3 MB, characterized by MYC amplification, exhibits the poorest prognosis, with a high propensity for metastasis and recurrence. Our previous research identified WEE1 as a critical regulator of MB cell survival and found that Myc-driven MB is particularly sensitive to the WEE1 inhibitor AZD1775. Although AZD1775 has demonstrated efficacy, especially when combined with genotoxic agents, resistance to small molecule inhibitors often emerges, limiting its therapeutic potential. CDK7, a kinase essential for transcriptional initiation via phosphorylation of RNA Pol II’s C-terminal domain, plays a critical role in Myc-driven malignancies and is frequently enriched at super-enhancers. AZD1775-resistant cells undergo chromatin reorganization to establish alternate cis-acting elements that promote transcription of DNA repair and proliferation genes, circumventing treatment. We hypothesized that targeting CDK7-mediated transcriptional reprogramming could overcome AZD1775 resistance. Using the CDK7 inhibitor THZ1, we performed western blot analysis of DNA repair proteins and observed inhibition of ATM pathway activation, a key component of the DNA damage response. Proliferation assays in both parental and AZD1775-resistant cell lines demonstrated that combining AZD1775 with THZ1 significantly suppressed cell growth. These findings suggest that THZ1 may reverse adaptive chromatin reorganization, sensitizing resistant MB cells to AZD1775 and enhancing the overall therapeutic response. Future studies will investigate the potential of combining CDK7 inhibitors with other epigenetic modulators to further disrupt resistance mechanisms and improve treatment outcomes in aggressive MB subtypes, particularly Group 3 MB. This approach offers a promising avenue for overcoming therapeutic resistance and advancing precision medicine in medulloblastoma.