SELECTIVE REQUIREMENT OF PI3K/PDK1 SIGNALING FOR KRAS ONCOGENE-DRIVEN PANCREATIC CELL PLASTICITY AND CANCER
Stefan Eser, Nina Reiff, Marlena Messer, Barbara Seidler, Kathleen Gottschalk, Melanie Dobler, Maren Hieber, Andreas Arbeiter, Sabine Klein, Bo Kong, Christoph W. Michalski, Anna Melissa Schlitter, Irene Esposito, Alexander J. Kind, Lena Rad, Angelika E. Schnieke, Manuela Baccarini, Dario R. Alessi, Roland Rad, Roland M. Schmid, Günter Schneider, Dieter Saur. (18-03-2013).Cancer Cell
Research Area C
Oncogenic Kras activates a plethora of signaling pathways, but our understanding of critical Ras effectors is still very limited. We show that cell-autonomous phosphoinositide 3-kinase (PI3K) and 3-phosphoinositide-dependent protein kinase 1 (PDK1), but not Craf, are key effectors of oncogenic Kras in the pancreas, mediating cell plasticity, acinar-to-ductal metaplasia (ADM), and pancreatic ductal adenocarcinoma (PDAC) formation. This contrasts with Kras-driven non-small cell lung cancer, where signaling via Craf, but not PDFK1, is an essential tumor-initiating event. These in vivo genetic studies together with pharmacologic treatment studies in models of human ADM and PDAC demostrate tissue-specific differences of oncogenic Kras signaling and define PI3K/PDK1as a suitable target for therapeutic intervention specifically in PDAC.