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NLRP4 drives olaparib resistance in pancreatic cancer
Mingming Xiao1,2,3,4,5, Xianjun Yu1,2,3,4,5, Si Shi1,2,3,4,5
1Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
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.
Insights
NLRP4 upregulation increases resistance to olaparib in pancreatic cancer by enhancing DNA repair and autophagy. Inhibiting NLRP4, ROS, or autophagy may improve olaparib treatment effectiveness.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Olaparib is approved for metastatic pancreatic cancer with BRCA mutations.
- Resistance to olaparib is a significant clinical challenge in pancreatic cancer.
- Understanding resistance mechanisms is key for developing improved targeted therapies.
Purpose of the Study:
- To investigate the role of NLRP4 (NLR family pyrin domain containing 4) in olaparib resistance in pancreatic cancer.
- To elucidate the molecular mechanisms by which NLRP4 influences treatment response.
- To identify potential therapeutic strategies to overcome olaparib resistance.
Main Methods:
- Assessed NLRP4 expression in relation to olaparib resistance.
- Investigated NLRP4's involvement in DNA damage response (DDR) and autophagy.
- Examined the impact of inhibiting NLRP4, mitochondrial ROS, or autophagy on cancer cell sensitivity to olaparib.
Main Results:
- NLRP4 upregulation correlates with increased resistance to olaparib.
- NLRP4 enhances DNA repair capacity and promotes ROS production and autophagy upon olaparib treatment.
- Inhibition of mitochondrial ROS (MitoQ) or autophagy (chloroquine) sensitizes pancreatic cancer cells to olaparib.
Conclusions:
- NLRP4 promotes both autophagy and DNA repair, contributing to olaparib resistance.
- Targeting NLRP4, mitochondrial ROS, or autophagy may represent effective strategies to enhance olaparib efficacy.
- Low NLRP4 expression may predict a favorable response to olaparib treatment.
