Abstract 4493: Exploring APE1-G4 interactions and FACT complex inhibition to overcome therapy resistance in pediatric medulloblastoma

Abstract Medulloblastoma or MB is the most common malignant brain tumor in children. Tumor recurrence and therapy resistance remain critical obstacles for the treatment of MB. Although surgical resection followed by high doses of chemotherapies and ionizing radiation IR has considerably improved the survival rates. Resistance of residual tumor to IR and chemotherapies often leads to tumor recurrence. Despite advances in standard therapies, survival rates for relapsed MB patients have remained stagnant for over three decades, leaving clinicians and families with limited options. Previous reports have demonstrated that APE1, a key protein involved in repairing AP sites and single-strand breaks SSBs in DNA, is overexpressed in MB, and its activity is associated with tumor progression. Knockdown of APE1 enhances sensitivity of MB cells to radiation and chemotherapy, suggesting that APE1 mediates IR/chemo resistance. We have recently demonstrated that IR or cisplatin treatment induced APE1 interaction which Facilitates Chromatin transcription FACT complex, and treatment with CBL0137, a FACT targeted small molecule, improves the potency of cisplatin and radiation in vitro and in intracranial orthotopic MB xenograft model. Our current study discovered that recombinant APE1 binds to non-canonical four stranded DNA secondary structure called G quadruplexes or G4 DNA in the genome of MB cells and interacts with G4 in cells. Inhibition of APE1 binding to G4 by small molecules affects damage repair in cells. Treatment with these small molecules dose-dependently affects MB tumor cell growth in vitro. Further, we have delineated a mechanistic link of G4 with APE1 mediated drug resistance. Our project unraveled a novel mechanism by which APE1 and G4 promote therapy resistance and identify a promising strategy to improve the efficacy of IR and cisplatin and prevent tumor recurrence. Citation Format: Ritesh Dey, Yingling Chen, Sutapa Ray, Kishor Bhakat. Exploring APE1-G4 interactions and FACT complex inhibition to overcome therapy resistance in pediatric medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4493.