The RAS oncogene, which is mutated in over 95% of pancreatic cancers, relies on reactive oxygen species (ROS) to invoke oncogenic signaling that allows tumor cells to proliferate and survive. However excess ROS can also kill or proliferatively arrest cancer cells through oxidative stress and DNA damage. Thus RAS-driven cancer cells elevate redox-protective adaptations to enable ROS-driven signaling but prevent ROS-driven tumor inhibition. The mammalian Nudix pyrophosphatase MTH1(MutT Homolog 1), which eliminates oxidized nucleotides to prevent their incorporation as oxidative damage into the genome, is a critical redox-protective adaption in RAS-driven tumor cells. Our lab has previously shown that depletion of MTH1 alters the ability of RAS-driven cancer cells to drive ROS-driven signaling. In pancreatic cancer, a major ROS oncogenic signaling hub is the epidermal growth factor receptor (EGFR) pathway, which regulates factors such as growth, proliferation, and differentiation through RAS. We hypothesized reducing redox protection from MTH1 would compromise this pathway. We found that depleting MTH1 using small hairpin RNAs (shRNA) in pancreatic cancer cell lines reduces their proliferative ability. This inhibition is associated with a decrease in EGFR expression. Interestingly analysis of PDAC (pancreatic ductal adenocarcinoma) patient datasets showed MTH1 and EGFR levels are positively correlated. Thus MTH1 inhibition could supplement or even replace EGFR inhibitors as treatment possibilities in pancreatic cancer, which has few durable treatment options and is fatal.
