PARP inhibitors (PARPi), such as Olaparib are designed by exploiting Synthetic Lethality in 10% of the population in treating BRCA-mutated pancreatic cancer. Despite the promise of PARP inhibitors (PARPi), clinical outcomes are compromised by rapid resistance in all cases of cancer and remains a universal barrier to survival. we identify SETDB1, an epigenetic regulator and histone methyltransferase, as a novel co-therapeutic target that mediates resistance to PARP1 inhibition in pancreatic ductal adenocarcinoma (PDAC). To identify the molecular escape mechanisms that allow these cells to bypass PARP1 inhibition, we performed a multi-cohort transcriptomic analysis. By utilizing TCGA-19000 genes and QCMG- 16,000 genes, we isolated 19 genes that were co-expressed with PARP1. Among the co-expressed cohort, SETDB1 emerged as a primary candidate (R=0.75, p<0.001) showing a strong positive correlation with PARP1 expression and poor clinical outcomes. Functional implications of these gene signatures, performed through Gene Set Enrichment Analysis (GSEA) and DAVID Gene Ontology (GO) analysis, revealed that PARP1 high PDAC was significantly enriched in pathways related to the nucleoplasm (9.93), Ubl conjugation, chromatin remodeling, and DNA damage repair. SETDB1 knockdown significantly potentiated growth inhibition and sensitized PDAC cells to Olaparib, increasing the proportion of apoptotic cells and reducing proliferation compared to either treatment alone, consistent with chromatin-mediated suppression. Furthermore, we validated the clinical relevance of the findings across distinct datasets and identified SETDB1 as a consistently overexpressed gene in PARP1-high PDAC, with higher expression associated with lower disease-free survival. In vitro validation in PANC-1 models showed SETDB1 as a potential co-therapeutic target to enhance PARP inhibitor sensitivity and can fulfill the concept of synthetic lethality for all PDAC patients.
Aarush Shah (Sat,) studied this question.