AKT-independent Signaling Downstream of Oncogenic PIK3CA Mutations in Human Cancer

Cancer Cell. 2009 Jul 7;16(1):21-32. doi: 10.1016/j.ccr.2009.04.012.

Abstract

Dysregulation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway occurs frequently in human cancer. PTEN tumor suppressor or PIK3CA oncogene mutations both direct PI3K-dependent tumorigenesis largely through activation of the AKT/PKB kinase. However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth. Instead, these cells retain robust PDK1 activation and membrane localization and exhibit dependency on the PDK1 substrate SGK3. SGK3 undergoes PI3K- and PDK1-dependent activation in PIK3CA mutant cancer cells. Thus, PI3K may promote cancer through both AKT-dependent and AKT-independent mechanisms. Knowledge of differential PI3K/PDK1 signaling could inform rational therapeutics in cancers harboring PIK3CA mutations.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Breast Neoplasms / enzymology
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / physiopathology
  • Cell Line, Tumor
  • Cell Survival / genetics
  • Class I Phosphatidylinositol 3-Kinases
  • Enzyme Activation
  • Female
  • Gene Expression Profiling
  • Humans
  • Mutation*
  • Neoplasms / genetics*
  • Neoplasms / metabolism
  • PTEN Phosphohydrolase / deficiency
  • PTEN Phosphohydrolase / genetics
  • Phosphatidylinositol 3-Kinases / genetics*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / physiology*
  • Pyruvate Dehydrogenase (Acetyl-Transferring) Kinase
  • Signal Transduction / genetics

Substances

  • PDK1 protein, human
  • Pyruvate Dehydrogenase (Acetyl-Transferring) Kinase
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • SGK3 protein, human
  • PTEN Phosphohydrolase
  • PTEN protein, human