Thursday, October 17, 2024
10/17/2024
ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with limited treatment options. The overall 5-year survival rate is only 11% and there is an unmet need for better therapies. For patients with homologous recombination repair (HRR) deficient tumors (BRCA1/2, PALB2), poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi)/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. This underscores a dire need to identify new targets to enhance the sensitivity of these promising agents and expand the PDAC patient population that could benefit from them. We recently discovered that BARD1 (BRCA1- Associated- Ring- Domain- 1), an obligate binding partner of BRCA1 and a key factor in HR, is upregulated in PDAC cells under DNA damage conditions (Jain et al Cancers (Basel) 6;14(7):1848, 2022). We found that deletion of BARD1 rendered PDAC cells (HRR proficient) extremely sensitive to PARPi/platinums and enhanced DNA damage. Although, these effects may be attributed to BARD1’s canonical role in HRR, transcriptome profiling of BARD1 silenced cells suggests BARD1 has pleiotropic effects on cellular functions linked to cell cycle, cellular senescence, and DNA replication. In line with these predictions, we noted that BARD1 silencing strongly reduced cell proliferation, decreased clonogenic capacity in vitro, slowed tumor growth in vivo of PDAC cells and reduced expression of several cell cycle proteins, notably Polo-Like-Kinase-1 (PLK-1). PLK-1 is a serine threonine kinase that strongly promotes the progression of cells through mitosis. PLK-1 is overexpressed in PDAC and deregulation of PLK-1 activity contributes to genetic instability, which in turn leads to oncogenic transformation. We hypothesize that PLK-1 interacts with BARD1 and this interaction is necessary for PDAC cell response to DNA damage agents. We will test our hypothesis through two specific aims. In aim 1, we will determine the molecular interaction of BARD1 and PLK-1 in PDAC cells using biochemical assays, and in aim 2, we will determine if BARD1’s regulation of PLK-1 in PDAC cells is a driver of response to DNA damage agents, using overexpression systems in a murine model. The overarching goal of this project is to elucidate the role and significance of BARD1-PLK-1 interaction in PDAC and therapy response to DNA damage agents. The completion of this project will lay the groundwork for development of novel targeted therapeutic strategies against PDAC, and in the future could be applied to other cancer types as well. Keywords: Pancreatic ductal adenocarcinoma, DNA damage, cell cycle, BARD1
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