PI3K and cancer: lessons, challenges and opportunities

Nat Rev Drug Discov. 2014 Feb;13(2):140-56. doi: 10.1038/nrd4204.

Abstract

The central role of phosphoinositide 3-kinase (PI3K) activation in tumour cell biology has prompted a sizeable effort to target PI3K and/or downstream kinases such as AKT and mammalian target of rapamycin (mTOR) in cancer. However, emerging clinical data show limited single-agent activity of inhibitors targeting PI3K, AKT or mTOR at tolerated doses. One exception is the response to PI3Kδ inhibitors in chronic lymphocytic leukaemia, where a combination of cell-intrinsic and -extrinsic activities drive efficacy. Here, we review key challenges and opportunities for the clinical development of inhibitors targeting the PI3K-AKT-mTOR pathway. Through a greater focus on patient selection, increased understanding of immune modulation and strategic application of rational combinations, it should be possible to realize the potential of this promising class of targeted anticancer agents.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Clinical Trials as Topic
  • Drug Discovery* / methods
  • Drug Discovery* / trends
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • Humans
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology*
  • Neoplasms / pathology
  • Phosphoinositide-3 Kinase Inhibitors*
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Receptor Cross-Talk / drug effects
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / antagonists & inhibitors

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Phosphoinositide-3 Kinase Inhibitors
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt