Abstract 118: GPR68, a proton-sensing GPCR that mediates interaction of pancreatic cancer associated fibroblasts and cancer cells, is a potential therapeutic target for pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense fibrotic stroma (desmoplasia) that is generated by pancreatic cancer associated fibroblasts (PCAFs) derived from pancreatic stellate cells (PSCs) and pancreatic fibroblasts (PFs). We discovered that GPR68, a proton-sensing GPCR, has much higher expression in PCAFs compared to either PFs or PSCs. GPR68 activation in PCAFs enhances interleukin-6 (IL-6) expression via a cAMP/PKA/CREB signaling pathway. GPR68 knockdown with siRNA decreased low pH-induced IL-6 production by PCAFs and increased the proliferation of PDAC cells by PCAF conditioned media. Ogerin, a GPR68 positive allosteric modulator, enhanced the pH-dependent increase in cAMP in PCAFs. A pilot screening of 96 GPCR-specific compounds tested with GPR68-overexpressing HEK293 cells identified two compounds (C1 and C2) that decrease intracellular cAMP at pH6.4, but not isoproterenol (β-adrenergic receptor)-induced cAMP, implying their selective antagonism of GPR68. Furthermore, compound C2 decreased low pH-induced IL-6 levels in the conditioned media of GPR68-overexpressing HEK293 cells We conclude that GPR68 in PCAFs detects low pH, contributes to PDAC cell-PCAF interaction and may be a novel therapeutic target for pancreatic cancer. Note: This abstract was not presented at the meeting. Citation Format: Shu Z. Wiley, Krishna Sriram, Cristina Salmeron-Salvador, Hiroshi Nishihara, Randall French, Andrew M. Lowy, Paul A. Insel. GPR68, a proton-sensing GPCR that mediates interaction of pancreatic cancer associated fibroblasts and cancer cells, is a potential therapeutic target for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 118.