Mechanisms of resistance to WEE1 inhibition in Myc driven medulloblastoma

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PROJECT SUMMARY Medulloblastoma (MB) is the most prevalent malignant brain tumor in children and demonstrates high level of heterogeneity. Treatment for MB includes chemotherapy and radiation often resulting in long-term morbidity. MYC driven MB in particular are high risk tumors with poor long-term survival. We previously identified WEE1 as a target in MYC driven MB. WEE1 regulates MYC driven replication stress and high throughput chemical screening identified high degree of synergy with gemcitabine. Further data suggest that MB tumors become resistant to WEE 1 inhibition and that this mechanism is mediated by CDK7.. We hypothesize CDK7 re-sensitizes MB cells to WEE1 inhibition by reprograming the enhancer landscape to alter metabolic pathways and suppressing homologous recombination DNA repair networks. To CDK7 that inhibition of inhibition MB and homologous targeting approaches for validate inhibition in combination with WEE1 as a therapeutic strategy we will pursue three key questions. 1. How dose CDK7 alter enhancer landscape to modulate sensitivity to WEE1 inhibition? 2. Is combination of WEE1 CDK7 inhibition therapeutically effective in MB in vivo? 3. Can addition of agents that target recombination mediated DNA repair potentiate CDK7/WEE1 mediated therapeutic of MB? The results of this work are expected to yield important insights into that could be used to inhibit MYC function in high-risk MB, and provide a rationale the treatment of MYC driven MB, which represents the long-term goal of our research.