Development of PI3K Inhibitors: Lessons Learned From Early Clinical Trials

Nat Rev Clin Oncol. 2013 Mar;10(3):143-53. doi: 10.1038/nrclinonc.2013.10. Epub 2013 Feb 12.

Abstract

The phosphatidylinositol 3-kinase (PI3K) pathway has an important role in cell metabolism, growth, migration, survival and angiogenesis. Drug development aimed at targetable genetic aberrations in the PI3K/AKT/mTOR pathway has been fomented by observations that alterations in this pathway induce tumour formation and that inappropriate PI3K signalling is a frequent occurrence in human cancer. Many of the agents developed have been evaluated in early stage clinical trials. This Review focuses on early clinical and translational data related to inhibitors of the PI3K/AKT/mTOR pathway, as these data will likely guide the further clinical development of such agents. We review data from those trials, delineating the safety profile of the agents--whether observed sequelae could be mechanism-based or off-target effects--and drug efficacy. We describe predictive biomarkers explored in clinical trials and preclinical mechanisms of resistance. We also discuss key unresolved translational questions related to the clinical development of inhibitors of the PI3K/AKT/mTOR pathway and propose designs for biomarker-driven trials to address those issues.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Biomarkers
  • Clinical Trials as Topic
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / physiology
  • Mice
  • Mice, Transgenic
  • Molecular Targeted Therapy*
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / physiology
  • Phosphoinositide-3 Kinase Inhibitors*
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein Processing, Post-Translational / drug effects
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / physiology
  • Signal Transduction / drug effects*
  • Signal Transduction / genetics
  • Sirolimus / pharmacology
  • Sirolimus / therapeutic use
  • Substrate Specificity
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / physiology

Substances

  • Antineoplastic Agents
  • Biomarkers
  • Isoenzymes
  • Neoplasm Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • AKT1 protein, human
  • Proto-Oncogene Proteins c-akt
  • Sirolimus