Abstract PR007: Overcoming drug resistance in Sonic hedgehog-driven medulloblastoma

Abstract

Medulloblastoma (MB) is the most common malignant brain tumor in children, and the Group 2 (Sonic Hedgehog; SHH) subtype is driven by aberrant activation of the SHH signaling pathway. Several FDA-approved therapies target oncogenic SHH signaling by inhibiting SMOOTHENED (SMO), the primary membrane-associated regulator of the pathway. Although SHH MBs often exhibit initial clinical responses to SMO inhibitors, efficacy is limited by the rapid emergence of resistance-conferring SMO mutations. Leveraging recent mechanistic insights into SMO activation obtained through integrated structural biochemistry and deep mutational scanning, we have identified previously unrecognized vulnerabilities that suggest strategies to overcome SMO-mediated resistance. We will discuss evidence demonstrating that G protein–coupled receptor kinases 2 and 3 (GRK2/3) are essential downstream effectors of oncogenic SMO signaling in MB and required for GLI-dependent transcriptional activation. We will also present findings that evaluate GRK2/3 inhibition as a new therapeutic strategy to overcome resistance to SMO inhibitors in MB using complementary animal and cell-based models of SHH MB, including newly developed zebrafish MB models for high-throughput in vivo screening.