Abstract PR11: KRAS mutant-specific interactions reveal mechanisms in pancreatic cancer tumorigenesis and metabolic function
Authors: Kamala Sundararaj, Rachel Burge, Samaneh Saberikashani, Lucas Bialousow, Amanda Linke, Merissa Smith, Michael C. Ostrowski, John P. O'Bryan, G. Aaron Hobbs
Journal: Cancer Research (2024)

Abstract Mutational activation of the KRAS proto-oncogene is the initiating mutational event in pancreatic ductal adenocarcinoma (PDAC) and ~90% of patients harbor KRAS mutations. PDAC is marred by a 12% five-year overall survival rate, and developing effective therapeutic strategies remains a priority. Accumulating evidence suggests that all KRAS mutations are not created equal. While the KRASG12R mutation is rare in lung and colorectal cancers (&amp;lt;1%), it is the third most common KRAS mutation in PDAC, accounting for approximately 20% of all cases. However, KRASG12R cannot interact with the lipid kinase PI3Ka, a well-characterized RAS effector necessary for KRAS-driven tumorigenesis. Previous studies in mice models of cancer have demonstrated that ablation of the KRAS:PI3Ka interaction limits tumorigenesis. Despite the inability of KRASG12R to activate PI3Ka directly, AKT signaling is robustly activated in KRASG12R-mutant PDAC. The mechanisms that allow the KRASG12R mutant to overcome the inability to activate PI3K and promote PDAC are unclear. We recently developed a Ptf1a-CREERT2;KrasLSL-G12R genetically engineered mouse model to study KRASG12R in an in vivo context. This model does not develop pancreas lesions or tumors. We have uncovered two unique characteristics of human PDAC that we hypothesize allows for the KRASG12R mutation to produce tumors only in human pancreatic tissue. First, we have found that all four PI3K isoforms are overexpressed in human PDAC, and the PI3Kd and PI3Kg isoforms are specifically upregulated in KRASG12R-mutant PDAC. Second, PTEN is oxidized in PDAC. PTEN oxidation results in an intramolecular disulfide bond, which inhibits the phosphatase activity of PTEN and leads to hyperactivated PI3K signaling. Critically, mouse pancreas tissue only expresses the PI3Ka/b isoforms and PTEN is in the reduced state, demonstrating two significant differences between mouse models and human disease. Additionally, we have determined that PTEN becomes fully oxidized in nutrient-restricted medium (low glucose/glutamine), a common strategy employed to mimic the pancreatic tumor microenvironment in cell culture. Using PTEN oxidation-resistant variants, we demonstrate that KRASG12R-mutant PDAC cell lines are reliant on oxidized (inactivated) PTEN for proliferation. To confirm that PTEN inactivation can aid KRASG12R-mediated tumorigenesis in mouse models, we generated at KrasG12R/+;Ptenfl/fl genetically engineered mouse model, and the results of this model will be presented herein. Thus, our data demonstrate that increased PI3K isoform expression, coupled with PTEN oxidation, creates a unique environment that allows KRASG12R to initiate and promote pancreatic tumorigenesis. As PTEN oxidation overcomes the need for KRAS to activate PI3K signaling in PDAC, these results indicate that directly targeting KRAS alone will be insufficient at reducing tumor growth in humans and clinically successful therapeutic strategies will have to develop alternative methods to reduce PI3K signaling in addition to directly targeting KRAS activity. Citation Format: Kamala Sundararaj, Rachel Burge, Samaneh Saberikashani, Lucas Bialousow, Amanda Linke, Merissa Smith, Michael C. Ostrowski, John P. O'Bryan, G. Aaron Hobbs. KRAS mutant-specific interactions reveal mechanisms in pancreatic cancer tumorigenesis and metabolic function [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr PR11.