PTEN Oxidation Promotes Constitutive PI3K Signaling and Inducible Macropinocytosis in Pancreatic Cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is defined by the near universal occurrence of KRAS mutations. The KRASG12R mutation is detected in approximately 15% to 20% of patients with PDAC and rare in other KRAS-mutant cancers. KRASG12R is unable to activate the lipid kinase PIK3CA, suggesting that alternative mechanisms might be employed to activate KRASG12R-independent PI3K signaling in PDAC. In this study, we detected elevated expression of all four PI3K isoforms in PDAC cell lines, with the PIK3CG isoform showing higher overall expression in KRASG12R-mutant PDAC. All four PI3K isoforms contributed to global PI3K signaling, and inhibition of any single isoform was insufficient to limit PDAC proliferation. The combined inhibition of all PI3K isoforms was required to limit proliferation, providing a potential explanation for the limited efficacy of PI3K inhibitors in the clinic. Additionally, PTEN, a negative regulator of PI3K signaling, was inactivated in PDAC by the formation of an intramolecular disulfide, which elevated overall PI3K signaling and reduced the dependency of PI3K signaling on KRAS. Oxidation of PTEN was independent of KRAS mutation status. Finally, nutrient-limiting conditions mimicking the PDAC tumor microenvironment further elevated PTEN oxidation and significantly increased macropinocytosis. Thus, this study uncovered a mechanism that supports elevated PI3K signaling in PDAC, thereby reducing the need for KRAS to directly activate the PI3K pathway. Significance: PTEN inactivation by intramolecular disulfide bond formation and elevated expression of PI3K isoforms in pancreatic cancer leads to unchecked KRAS-independent PI3K signaling, highlighting the need for therapeutic approaches targeting constitutive PI3K signaling.