Abstract B006: Targeting BARD1 in human pancreatic ductal adenocarcinoma: How to expand the target population of vulnerable tumors?

作者：Aditi Jain, Rutuj P. Kusurkar, Eleanor Jenkins, Avinoam Nevler, Wei Jiang, Charles J. Yeo · 发表于：Cancer Research · 年份：2024 · DOI：10.1158/1538-7445.dnarepair24-b006 · 研究领域：DNA Repair Mechanisms、Cancer Genomics and Diagnostics、CRISPR and Genetic Engineering

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the deadliest malignancy of the pancreas, with an overall five-year survival rate of only 12%. Despite therapeutic advances, effective therapies are still limited. It is now known that many of the DNA damage repair (DDR) genes that are mutated in PDAC are crucial for the proper functioning of the homologous recombination repair (HRR) pathway. Loss-of-function alterations in DDR genes such as BRCA1/2 mutations render PDAC cells vulnerable to certain DNA damage agents, for example, poly (ADP-ribose) polymerase inhibitors (PARPi) and platinum-based agents. Since this treatment strategy is currently limited to only 5-10% of PDAC patients, it underscores a dire need to find new therapeutic avenues and expand the PDAC patient population that could benefit from these therapies. We have recently published that BARD1 (BRCA1- Associated- Ring- Domain- 1), an obligate binding partner of BRCA1 in the process of HRR, is upregulated in PDAC cells exposed to PARPi/platinums. PDAC tissue microarray stained for BARD1 also shows higher BARD1 expression in PDAC tissues compared to normal pancreas. Here, we explored the effects of targeting BARD1 on PDAC cells. For this, we created genetic models of BARD1 inhibition and utilized these model systems to study if loss of BARD1 slows PDAC growth, invasion, and chemo-sensitizes PDAC cells to PARPis and DNA damage agents. Doxycycline inducible shRNA and BARD1 CRISPR KO models were created to inhibit ...