PI3K and mTOR signaling pathways in cancer: new data on targeted therapies

Curr Oncol Rep. 2012 Apr;14(2):129-38. doi: 10.1007/s11912-012-0227-y.

Abstract

The mammalian target of rapamycin (mTOR) and the phosphoinositide 3-kinase (PI3K) signaling pathways are commonly deregulated in cancers and promote cellular growth, proliferation, and survival. mTOR is part of two complexes, mTORC1 and mTORC2, with different biochemical structures and substrates specificity. PI3K/AKT activation may result from genetic hits affecting different components of the pathway, whereas the mechanisms leading to constitutive mTORC1 activation remain globally unknown. The connections between the PI3K and mTOR kinases are multiple and complex, including common substrates, negative feedback loops, or direct activation mechanisms. First-generation allosteric mTOR inhibitors (eg, rapamycin) are mainly active on mTORC1 and mostly display cytostatic anti-tumor activity. Recently, second-generation catalytic mTOR inhibitors targeting both mTOR complexes 1 and 2 have been developed. Some of them also inhibit class IA PI3K. Here, we highlight recent data generated with these new inhibitors against cancer cells and their potential as anti-cancer drugs.

Publication types

  • Review

MeSH terms

  • Clinical Trials as Topic
  • Drug Evaluation, Preclinical
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Molecular Targeted Therapy / methods*
  • Multiprotein Complexes
  • Neoplasms / drug therapy*
  • Neoplasms / physiopathology
  • Phosphatidylinositol 3-Kinases / physiology
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Proteins / antagonists & inhibitors
  • Proteins / physiology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / physiology
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / physiology

Substances

  • CRTC2 protein, human
  • Multiprotein Complexes
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Proteins
  • Transcription Factors
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1