Abstract C048: Benzodiazepines modify the pancreatic ductal adenocarcinoma tumor microenvironment

Abstract Benzodiazepines (BZDs) are a class of drugs commonly prescribed to pancreatic ductal adenocarcinoma (PDAC) patients to treat anxiety, anticipatory nausea prior to chemotherapy, and insomnia. We discovered that approximately 1 in 4 pancreatic cancer patients are prescribed BZDs and that significant differences in survival outcomes are associated with the type of BZD prescribed. Lorazepam is associated with poorer recurrence-free survival (HR 3.83 (1.53,9.57)) while alprazolam is associated with improved recurrence-free survival (HR 0.38 (0.16,0.92)). We hypothesize that these differences in survival result from off-target activation of the proton-sensing GPCR, GPR68, by n-unsubstituted BZDs, such as lorazepam. GPR68 is preferentially expressed in PDAC cancer-associated fibroblasts (CAFs). We found that n-unsubstituted BZDs commonly prescribed to PDAC patients potentiate activation of GPR68 in the presence of acidity, subsequently promoting secretion of IL-6 by CAFs in a GPR68-dependent manner. Conversely, we found that n-substituted BZDs, such as alprazolam, decrease IL-6 secretion by CAFs in a GPR68-independent manner. Using a syngeneic KPC transplant model, we found that tumors from mice treated with lorazepam had increased expression of inflammatory signaling pathways and ECM-related genes by RNA sequencing. Histologically, lorazepam-treated tumors had increased levels of collagen, alpha-smooth muscle actin staining, and high levels of ischemic necrosis in the centers of the tumors. Overall, these findings indicate that benzodiazepines can modify the PDAC tumor microenvironment, which may subsequently impact chemotherapeutic efficacy and patient survival. Citation Format: Abigail C. Cornwell, Abdulrahman A. Alahmari, Arwen A. Tisdale, Kathryn Maraszek, Swati Venkat, Michael E. Feigin. Benzodiazepines modify the pancreatic ductal adenocarcinoma tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C048.