Roles for KRAS in Pancreatic Tumor Development and Progression

Abstract

The Kras gene is mutated to an oncogenic form in most pancreatic tumors. However, early attempts to use this molecule as a specific biomarker of the disease, or inhibit its activity as a cancer therapy, failed. This left a situation in which everyone was aware of the association between this important oncogene and pancreatic cancer, but no one knew what to do about it. Recent findings have changed this picture—many assumptions made about KRAS and its role in pancreatic cancer were found to be incorrect. Several factors have contributed to increased understanding of the activities of KRAS, including creation of genetically engineered mouse models, which have allowed for detailed analyses of pancreatic carcinogenesis in an intact animal with a competent immune system. Cancer genome sequencing projects have increased our understanding of the heterogeneity of individual tumors. We also have a better understanding of which oncogenes are important for tumor maintenance and are therefore called “drivers.” We review the advances and limitations of our knowledge about the role of Kras in development of pancreatic cancers and the important areas for future research.

Oncogenic KRAS Targets MUC16/CA125 in Pancreatic Ductal Adenocarcinoma

“…Oncogenic mutation of Kras resulted in constitutive activation of RAS proteins which permanently bound to GTP and led to subsequent activation of signaling pathways, such as the PI3K/AKT/mTOR or RAF/MEK/ERK signaling pathway. The activation of these pathways was involved in transformation, uncontrolled proliferation, invasion, and metastasis of pancreatic cancer cells (28). Detection of the Kras mutation status could be used to assess prognosis of pancreatic cancer (29)(30)(31).…”

Functional implication of Dclk1 and Dclk1-expressing cells in cancer

“…21,22 The functional importance of mutant Kras, a member of the GTPase enzyme family, in pancreatic cancer, even in the setting of metastatic disease, has been shown in a series of seminal papers. [23][24][25] Consequently, the finding by Sureban and coworkers that siRNA-mediated knockdown of Dclk1 in human pancreatic cancer cells resulted in downregulation of Kras expression was of great interest.…”

Repurposing of Metformin and Aspirin by Targeting AMPK-mTOR and Inflammation for Pancreatic Cancer Prevention and Treatment

“…In addition, inflammation mediates suppression of immunosurveillance through inflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) produced by oncogenic Kras-expressing pancreatic neoplastic cells (12). Inflammation could also inhibit oncogene-induced senescence, stimulate the epithelial-mesenchymal transition, amplify and prolong Ras activity, and promote oncogenic mutagenesis, all of which contribute to PDAC initiation, development, and metastasis (14). Taken together, these observations support the importance of pancreatic inflammation, mediated by cytokines, reactive oxygen species, and unregulated proinflammatory pathways, for the development and progression of human pancreatic malignancy.…”

“…NFkB is constitutively activated in 70% of human pancreatic cancer and in many human pancreatic cancer cell lines, but not in normal pancreatic tissues or in immortalized, nontumorigenic pancreatic epithelial cells (55,56). It has been shown that NFkB signaling is activated by oncogenic Kras or by cytokines secreted from malignant or tumor-infiltrating immune cells in PDAC (14). Furthermore, inhibition of constitutive NFkB activity by a phosphorylation-defective IkBa (S32, 36A; IkBaM) suppresses pancreatic tumorigenesis in an orthotopic nude mouse model (57).…”