of Murine Pancreatic Epithelial Cells Requires MEK/ERK-Stimulated IGF1R Signaling

Mutation of KRAS is a common initiating event in pancreatic ductal adenocarcinoma (PDAC). Yet, the specific roles of KRAS-stimulated signaling pathways in the transformation of pancreatic ductal epithelial cells (PDEC), putativecellsoforiginfor PDAC,remainunclear. Here,weshowthat KRAS G12D andBRAF V600E enhancePDEC proliferation and increase survival after exposure to apoptotic stimuli in a manner dependent on MEK/ERK and PI3K/AKT signaling. Interestingly, we find that activation of PI3K/AKT signaling occurs downstream of MAP– ERK kinase (MEK), and is dependent on the autocrine activation of the insulin-like growth factor (IGF) receptor (IGF1R)byIGF2.Importantly,IGF1RinhibitionimpairsKRAS G12D -andBRAF V600E -inducedsurvival,whereas ectopic IGF2 expression rescues KRAS G12D - and BRAF V600E -mediated survival downstream of MEK inhibition. Moreover, we show that KRAS G12D - and BRAF V600E -induced tumor formation in an orthotopic model requires IGF1R.Interestingly,weshowthatwhileindividualinhibitionofMEKorIGF1RdoesnotsensitizePDACcellsto apoptosis, their concomitant inhibition reduces survival. Our findings identify a novel mechanism of PI3K/AKT activation downstream of activated KRAS, illustrate the importance of MEK/ERK, PI3K/AKT, and IGF1R signalinginpancreatictumorinitiation,andsuggestpotentialtherapeuticstrategiesforthismalignancy.MolCancer Res; 10(9); 1228–39. � 2012 AACR.