Abstract 3319: Evaluating and targeting DNA repair defects in pediatric high grade glioma

Abstract Homologous recombination deficiency (HRD) has been extensively studied in breast cancer and ovarian cancer given its correlation with sensitivity to Poly (ADP-ribose) polymerases (PARP) inhibitors. In these cancers, HRD is most frequently caused by biallelic inactivation of BRCA1/2 and these tumors often exhibit ‘genomic scars’ (Nik-Zainal, 2016; Telli, 2016; Davies, 2017). Our group profiled a cohort of 255 pediatric high-grade glioma (pHGG) patient samples for DNA damage response (DDR) gene variants and genomic scars. We found no evidence of BRCA1/2 loss in any sample, but we did detect evidence for HRD-associated genomic scars in 30% of our samples. Interestingly, we also detected biallelic loss of ATM, which is reported to be synthetically lethal with ATR inhibition (Marwan, 2016). Given these findings, our group set out to answer the following questions: 1) Does the presence of BRCA deficiency or HRD-related genomic scars predict sensitivity to PARP inhibition in pHGG tumors? 2) Do the ATM mutations we found impair ATM pathway activation and confer radiosensitivity, and do they induce synthetic lethality with ATR inhibition? Overall, this work underscores the importance of looking beyond simple mutation status to identify robust biomarkers of drug response in pHGG tumors. Citation Format: Evan Savage, Ke Xu, Miaomiao Li, Jason Myers, Evadnie Rampersaud, Rebekah DeVries, Kamran Mohammad Zahid, Krista Millican, Yawei Hui, Ti-Cheng Chang, Gang Wu, Anang Shelat, Christopher Tinkle. Evaluating and targeting DNA repair defects in pediatric high grade glioma [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 3319.