KRAS^G12R-Independent Macropinocytosis in Pancreatic Cancer

Macropinocytosis is a critical route of nutrient acquisition in pancreatic cancer cells. Constitutive macropinocytosis is promoted by mutant KRAS, which activates the PI3Kα lipid kinase and RAC1, to drive membrane ruffling, macropinosome uptake and processing. However, our recent study on the KRAS^G12R mutant indicated the presence of a KRAS-independent mode of macropinocytosis in pancreatic cancer cell lines, thereby increasing the complexity of this process. We found that KRAS^G12R-mutant cell lines promote macropinocytosis independent of KRAS activity using PI3Kγ and RAC1, highlighting the convergence of regulation on RAC signaling. While macropinocytosis has been proposed to be a therapeutic target for the treatment of pancreatic cancer, our studies have underscored how little we understand about the activation and regulation of this metabolic process. Therefore, this review seeks to highlight the differences in macropinocytosis regulation in the two cellular subtypes while also highlighting the features that make the KRAS^G12R mutant atypical.