Abstract
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 PDK1, is an essential tumor-initiating event. These in vivo genetic studies together with pharmacologic treatment studies in models of human ADM and PDAC demonstrate tissue-specific differences of oncogenic Kras signaling and define PI3K/PDK1 as a suitable target for therapeutic intervention specifically in PDAC.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
3-Phosphoinositide-Dependent Protein Kinases
-
Adenocarcinoma / genetics
-
Adenocarcinoma / metabolism
-
Adenocarcinoma / pathology
-
Animals
-
Carcinoma, Pancreatic Ductal / genetics
-
Carcinoma, Pancreatic Ductal / metabolism
-
Carcinoma, Pancreatic Ductal / pathology
-
Cell Proliferation
-
Cell Transformation, Neoplastic / genetics
-
Cell Transformation, Neoplastic / metabolism
-
Cyclin-Dependent Kinase Inhibitor p16 / genetics
-
Cyclin-Dependent Kinase Inhibitor p16 / metabolism
-
Enzyme Activation
-
Humans
-
Indazoles / pharmacology
-
Lithostathine / metabolism
-
Metaplasia
-
Mice
-
Mice, Inbred NOD
-
Neoplasm Transplantation
-
Pancreatic Neoplasms / genetics
-
Pancreatic Neoplasms / metabolism*
-
Pancreatic Neoplasms / pathology
-
Phosphatidylinositol 3-Kinases / metabolism*
-
Protein Serine-Threonine Kinases / metabolism*
-
Proto-Oncogene Proteins / metabolism*
-
Proto-Oncogene Proteins p21(ras)
-
Signal Transduction
-
Sulfonamides / pharmacology
-
TNF Receptor-Associated Factor 3 / metabolism*
-
Transplantation, Heterologous
-
Tumor Cells, Cultured
-
ras Proteins / metabolism*
Substances
-
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine
-
Cyclin-Dependent Kinase Inhibitor p16
-
Indazoles
-
KRAS protein, human
-
Lithostathine
-
Proto-Oncogene Proteins
-
REG1A protein, human
-
Sulfonamides
-
TNF Receptor-Associated Factor 3
-
3-Phosphoinositide-Dependent Protein Kinases
-
PDPK1 protein, human
-
Pdpk1 protein, mouse
-
Protein Serine-Threonine Kinases
-
Proto-Oncogene Proteins p21(ras)
-
ras Proteins