PI3K Pathway Alterations in Cancer: Variations on a Theme

Oncogene. 2008 Sep 18;27(41):5497-510. doi: 10.1038/onc.2008.245.

Abstract

The high frequency of phosphoinositide 3-kinase (PI3K) pathway alterations in cancer has led to a surge in the development of PI3K inhibitors. Many of these targeted therapies are currently in clinical trials and show great promise for the treatment of PI3K-addicted tumors. These recent developments call for a re-evaluation of the oncogenic mechanisms behind PI3K pathway alterations. This pathway is unique in that every major node is frequently mutated or amplified in a wide variety of solid tumors. Receptor tyrosine kinases upstream of PI3K, the p110 alpha catalytic subunit of PI3K, the downstream kinase, AKT, and the negative regulator, PTEN, are all frequently altered in cancer. In this review, we will examine the oncogenic properties of these genetic alterations to understand whether they are redundant or distinct and propose treatment strategies tailored for these genetic lesions.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Enzyme Inhibitors / therapeutic use
  • Genes, erbB-2 / physiology
  • Genes, ras / physiology
  • Humans
  • Models, Biological
  • Mutation / physiology
  • Neoplasms / drug therapy
  • Neoplasms / genetics*
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / genetics
  • Nuclear Proteins / physiology
  • PTEN Phosphohydrolase / antagonists & inhibitors
  • PTEN Phosphohydrolase / genetics
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / physiology*
  • Phosphoinositide-3 Kinase Inhibitors
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics
  • Transcription Factors / physiology

Substances

  • Enzyme Inhibitors
  • Nuclear Proteins
  • PI3KCA protein, human
  • Phosphoinositide-3 Kinase Inhibitors
  • Transcription Factors
  • PTEN Phosphohydrolase
  • PTEN protein, human