Abstract
Olaparib has been approved as a treatment for metastatic pancreatic ductal adenocarcinoma in patients with BRCA1 (BRCA1 DNA repair associated) or BRCA2 mutations. However, a large portion of pancreatic cancer patients either exhibit inherent resistance or develop resistance over time. Understanding the molecular mechanisms that drive this resistance is crucial to develop more effective targeted therapies. In this study, we found that NLRP4 (NLR family pyrin domain containing 4) upregulation is associated with increased resistance to olaparib in pancreatic cancer. In addition, NLRP4 plays a role in both the DNA damage response (DDR) and autophagy. Specifically, NLRP4 enhances DNA repair capacity and leads to increased reactive oxygen species (ROS) production and autophagy upon olaparib treatment. Notably, NLRP4-generated mitochondrial ROS promote autophagy without directly impacting DNA damage. Inhibition of either mitochondrial ROS production with MitoQ or autophagy with chloroquine (CQ) could sensitize pancreatic cancer cells to olaparib. These findings emphasize NLRP4's role in promoting both autophagy and DNA repair in response to olaparib, suggesting that patients with low NLRP4 expression might respond more favorably to olaparib treatment.