Oncogenic KRAS Induces a CD44v9 Antioxidant System Associated with Chemoresistance in Genetically Engineered Human Pancreatic Ductal Adenocarcinoma Organoids

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with an approximate 8% 5-year survival rate. The high mortality rate is attributed to various factors including lack of screening techniques, unresponsiveness to standard of care therapies due to the complexity of the tumor microenvironment (TME). Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) occurs in approximately 94% of PDACs. KRAS mutation is an early oncogenic event in pancreatic cancer that is readily detectable in 25% and 38% of precancerous lesions PanIN-1A and PanIN-1B, respectively. Thus, KRAS mutation is likely an early and initiating event in human pancreatic cancer, but the exact mechanism by which this oncogenic event drives tumorigenesis is largely unknown. Evidence in the literature has shown that during PDAC tumorigenesis, oncogenic KRAS induces metabolic changes that lead to increased generation of mitochondrial reactive oxygen species (ROS). Among these antioxidant systems is the mechanism regulated by cell adhesion molecule Cluster of Differentiation (CD) 44 transmembrane glycoprotein (CD44), that suppresses the production of ROS, resulting in the therapeutic resistance, recurrence, and metastasis of tumors Oncogenic KRAS is known to upregulate antioxidant systems to balance ROS to levels at which they drive major signaling pathways that contribute to oncogenic transformation and tumor progression. Based on the scientific premise that CD44v9 is part of the xCT cysteine/glutamate transporter antioxidant system that promotes resistance to chemotherapy, we hypothesized that KRAS mutation induces CD44v9 via the proteins AKT and mTOR as an early oncogenic event.