Abstract B022: Interplay between the cellular dntp pool and dna double-strand break repair: a potential therapeutic target for refractory glioblastoma

Abstract Glioblastoma (GBM) is a deadly brain tumor resistant to double-strand break (DSB) -inducing therapeutics due to dysregulated DNA-repair. Ionizing radiation (IR) and some chemotherapeutics strategically target cancer cells by causing DNA-DSBs, resulting in cell death if left insufficiently repaired. Homologous Recombination (HR) is an error-free DSB-repair process consisting of proteins that are often dysregulated in GBM, causing overactive DNA-repair, therapy resistance, and poor patient outcomes. Proteins involved in the HR-repair process have been extensively investigated; however, therapeutic resistance remains common. Here, we provide an alternative approach to target DSB-resistant GBM by modulating the dNTP pool instead of only targeting DNA-repair proteins. Our goal is to understand the interplay between dNTP pools and DSB-repair. dNTPs are a necessary constituent to repair DSBs; however, the role of the dNTP pool in DNA damage repair is not fully understood. Previous research shows that the dNTP pool remains unchanged after inducing DSBs, highlighting the importance of a tightly regulated dNTP pool. Our results show that increasing the dNTP pool significantly increased apoptosis and reduced cancer cell viability after IR. We found that a higher cellular dNTP pool impaired HR-mediated DSB-repair by delaying DNA end-resection in HR. Filling this gap in our knowledge may provide new avenues to sensitize therapy-resistant cancers, enhancing the efficacy of DSB-inducing therapies. Citation Format: Dominique Monroe, Edidiong Usoro, Arilyn Williams, Shelby Aycox, Emily Steinbeck, Waaqo Daddacha. Interplay between the cellular dntp pool and dna double-strand break repair: a potential therapeutic target for refractory glioblastoma abstract. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84 (5 Suppl₁): Abstract nr B022.