PIKfyve regulates pH homeostasis and tumor growth in pancreatic cancer

PROJECT SUMMARY The current overall 5-year survival rate for pancreatic ductal adenocarcinoma (PDAC) is 13% and it is expected to become the second leading cause of cancer-related death. Given these poor statistics and the lack of effective therapies, novel approaches are needed in treating this disease. Targeting metabolic pathways specific to PDAC may be a relevant strategy in developing innovative treatments. Metabolic rewiring and nutrient scavenging, which support cancer cell proliferation and survival, contribute to disease aggressiveness in a tumor microenvironment that is poorly vascularized, nutrient-poor, and immunosuppressive. PIKfyve, a FYVE-finger containing phosphoinositide kinase, has been associated with membrane homeostasis and vesicle trafficking, where it is essential in driving endocytic maturation through the phosphorylation of phosphatidylinositol 3- phosphate (PI3P) to PI(3,5)P2 on endosome and endolysosome membranes. PIKfyve has been demonstrated to be a potential therapeutic target in multiple cancers including prostate, liver, and multiple myeloma but has not been comprehensively evaluated in PDAC. Pharmacological inhibition of PIKfyve is achieved via treatment with the small molecule apilimod, which has been shown to be cytotoxic in some cancer cells. This proposal evaluates PIKfyve as a therapeutic target in PDAC by assessing PIKfyve function on cell fitness and aggressiveness in vitro and evaluating the therapeutic effect of PIKfyve inhibition in vivo. My preliminary data suggest that inhibition and genetic knockdown of PIKfyve reduce PDAC cell proliferation and the effects are accompanied with the loss of pH homeostasis and blockade of macropinocytosis, a protein scavenging pathway active in PDAC. I will determine the mechanism by which PIKfyve activity contributes to cell fitness, metabolism, and aggressiveness. Moreover, the effect of PIKfyve on PDAC development will also be evaluated in vivo, expanding on preliminary studies in which PIKfyve inhibition reduced PDAC tumor size in an orthotopic syngeneic mouse model. The potential synergy of PIKfyve inhibitors with mechanism-specific drugs will also be evaluated in vivo. Combined, this study will provide mechanistic evidence and preclinical support for PIKfyve as a target in PDAC, potentially providing benefits to PDAC patients in the short-term since PIKfyve inhibition is currently being tested clinically for other indications.