EMBR-32. INTEGRATED STRESS RESPONSE PLAYS A PRO-SURVIVAL ROLE IN MYC-DRIVEN MEDULLOBLASTOMA

Abstract Medulloblastoma (MB) accounts for 20% of diagnosed brain tumors in children. Group 3 (G3) MB subtype is the most aggressive. Molecularly, G3 MB is characterized by MYC overexpression, which drives elevated mRNA translation in tumor cells. PERK is an eukaryotic translation initiation factor 2 (eIF2α) kinase that inhibits mRNA translation under endoplasmic reticulum (ER) stress conditions, such as in response to accumulation of unfolded proteins. When unfolded proteins accumulate in the ER, activated PERK phosphorylates eIF2α. This shuts down global translation and triggers integrated stress response (ISR) to help cells adapt through selective translation of mRNA encoding pro-survival proteins. High mRNA expression of PERK correlates with poor survival in G3 MB patients. In vitro, combination of ER or hypoxic stress with PERK knockdown induces apoptosis in MB cells. ISRIB is an ISR inhibitor that maintains translation rates despite eIF2α phosphorylation. Combining ISRIB with stress such as hypoxia induces apoptosis in MB cells and prevents accumulation of key ISR mediators such as ATF4. In addition, combination of ISRIB and hypoxia induces oxidative stress. Current G3 MB treatment regimens include vincristine, a known ISR inducer. Combination of ISRIB with vincristine amplifies vincristine-induced apoptosis, potentially suggesting novel therapeutic approach for MB. Our findings show that inhibition of ISR in G3 MB represents a powerful inducer of cancer cell death.