BARD1 is an exploitable therapeutic target for homologous repair proficient pancreatic ductal adenocarcinomas [PANC-1]

The overall 5-year survival rate of patients with pancreatic ductal adenocarcinoma (PDAC) is only 13% and there is an unmet need for better therapies. For the minority (5-10%) of patients with homologous recombination repair (HRR) deficient PDAC tumors (BRCA1/2, PALB2 mutations), poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) and platinum-based therapies offer the best-personalized treatment approach. However, the efficacy of these treatments is often limited due to inherent (HRR proficient tumors) or acquired drug resistance. We have previously shown that expression of BARD1 or BRCA1- Associated- Ring- Domain- 1, a DNA repair protein and an obligate binding partner of BRCA1, is post-transcriptionally upregulated by the pro-survival RNA binding protein HuR (ELAVL-1), in PDAC. Here, we evaluated BARD1’s functional role in PDAC cell biology and evaluated its potential as a therapeutic target in HRR-proficient PDAC. BARD1 expression was silenced in HRR- proficient PDAC cells using both small interfering RNAs and CRISPR/Cas9 deletion. Silencing BARD1 decreased cell proliferation and 3D matrigel invasion in vitro. Tumor growth of BARD1KO mouse xenografts was markedly impaired. Mechanistically, using RNA sequencing of BARD1 silenced cells, we found a de-enrichment of the epithelial-mesenchymal-transition (EMT) pathway and global downregulation of c-Myc-target genes, which control diverse cell signaling events in PDAC. BARD1 stabilized the c-Myc protein through inhibition of the ubiquitin–proteasome system. Further, to evaluate if BARD1 loss is synergistic with DNA damage agents, we employed a focused DNA damage drug library in BARD1 silenced cells and found that cells were uniquely sensitized to the PARP inhibitors class of drugs. Our proof-of-concept study implicates BARD1 as an attractive, exploitable therapeutic target for HRR proficient PDAC patients and presents a unique opportunity to expand the PDAC patient population that could benefit from PARP inhibitors in the clinical setting.