Oncogenic KRAS and the EGFR loop in pancreatic carcinogenesis-A connection to licensing nodes

Abstract

EGFR signaling has a critical role in oncogenic KRAS-driven tumorigenesis of the pancreas, whereas it is dispensable in other organs. The complex signaling network engaged by oncogenic KRAS and its modulation by EGFR signaling, remains incompletely understood. In order to study early signaling events activated by oncogenic KRAS in the pancreas, we recently developed a novel model system based on murine primary pancreatic epithelial cells enabling the time-specific expression of mutant Kras^G12D from its endogenous promoter. Here, we discuss our findings of a Kras^G12D-induced autocrine EGFR loop, how this loop is integrated by the MYC oncogene, and point to possible translational implications.

Keywords: EGFR; MYC; autocrine signaling; kras; pancreatic cancer.

Figure 1.

Expression of KRAS^G12D signaling in PDECs. Depicted is the genetic strategy to activate KRAS^G12D-expression in primary pancreatic ductal epithelial cells (PDECs) in a temporally controlled manner. Treatment of PDECs with 4-hydroxytamoxifen activates a Cre recombinase, expressed from the Rosa26 or the Hnf1b promoter. This leads to the expression of KRAS^G12D, driven by the endogenous promoter.

Figure 2.

Integration of oncogenic KRAS signaling by MYC in PDECs. GTP-bound oncogenic RAS induces several effector pathways. Depicted are the pathways with clear and definite impact on the carcinogenesis in the pancreas. Canonical signaling leads to activation of the RAF - (mitogen-activated kinase/ERK kinase) MEK - extracellular regulated kinase (ERK) protein kinase signaling pathway. Non-canonical signaling initiates the phosphoinositide 3-kinase (PI3Ks)-AKT-glycogen synthase kinase 3 (GSK3) cascade. ERK can phosphorylate MYC at serine 62 (S62), contributing to its stabilization and activity. AKT-mediated inhibitory phosphorylation of GSK3 impairs MYC threonine 58 (T58) phosphorylation and degradation. The KRAS^mut induced EGFR-loop increases MYC mRNA expression. The function of MYC to license growth and cell cycle entry is depicted.