Introduction: PARP inhibitors (PARPi) are known to have a synthetic lethal (SL) relationship with BRCA1/2 mutated cancers (ie: BRCA loss confers sensitivity to PARPi), but heterogeneity in response exists. PARPi have also found utility in BRCA-non mutated cancers, suggesting other factors may contribute to response. Recently, PARPi trials in pediatric solid tumors have had mixed results. SL interactions have been shown to exist in a network relationship, as such the aim of this study was to identify a clinically relevant SL signature (including synthetic dosage lethality and synthetic rescue) that would predict response to PARPi in pediatric cancers.

Methods: Pre-treatment genomic copy number alteration, RNA sequencing, and survival data from 519 pediatric cancer patients (INFORM Consortium, 91% solid tumor) were obtained. SL partner genes for PARPi were selected if co-alteration of the drug target (PARP1/2/3) and candidate gene was 1) found to be under-represented in the patient transcriptome, 2) associated with improved survival, and 3) the genes were phylogenetically similar to PARP1/2/3. The 100 gene signature was validated on two independent pediatric cancer drug screens: in-vivo orthotopic patient-derived xenograft (OPDX) mouse models (n=24) and in-vitro PRISM cell lines (n=54). It was also validated on a cisplatin (PARP surrogate) treated pediatric osteosarcoma clinical trial (n=37). Comparisons were made to 1) a signature generated with the same pipeline using adult TCGA data, 2) a validated adult synthetic lethality pipeline (SELECT), and 3) a published 60-gene PARPi response signature (BRCAness score).

Results: The pediatric signature predicted response in all drug screens evaluated. Four cell line screens: Talazoparib (AUC 0.72, p = 0.003), Rucaparib (AUC 0.69, p = 0.01), Niraparib (AUC 0.67, p = 0.03), Olaparib (AUC 0.64, p = 0.06), and two OPDX screens: Talazoparib (AUC 0.74, p = 0.03), Olaparib (AUC 0.74, p = 0.03). The pediatric signature outperformed both adult signatures (AUCs 0.34-0.61, all p’s >0.05), and the BRCAness score (AUCs 0.41-0.53, p’s >0.05) except in the Olaparib cell line (BRCAness: AUC 0.68, p = 0.01). In the pediatric osteosarcoma dataset, the pediatric signature predicted death (AUC 0.68) and two-year recurrence (AUC 0.72), outperforming the other measures (death: AUC 0.49-0.66; two-year recurrence: AUCs 0.36-0.44).

Discussion: We developed a pediatric derived, clinically relevant, synthetic lethal signature that predicts response to PARPi in pan-pediatric cancer drug screens and in a cisplatin treated osteosarcoma clinical trial. Our findings support the goal of identifying precision oncology frameworks to improve the care of children with cancer.

Citation Format: Matthew Nagy, Fiorella Schischlik, Kun Wang, Nishanth Ulhas Nair, E. Michael Gertz, Lipika R. Pal, Natalie Jaeger, Christopher Previti, Dina ElHarouni, Stefan M. Pfister, Eytan Ruppin. Predicting response to PARP inhibitors in pediatric cancer via synthetic lethal networks [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3118.