Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer

Cancer Cell. 2013 Mar 18;23(3):406-20. doi: 10.1016/j.ccr.2013.01.023. Epub 2013 Feb 28.

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.

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
  • Phosphatidylinositol 3-Kinases
  • 3-Phosphoinositide-Dependent Protein Kinases
  • PDPK1 protein, human
  • Pdpk1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins