Inhibition of the PI3K/AKT/mTOR Pathway in Solid Tumors

J Clin Oncol. 2016 Nov 1;34(31):3803-3815. doi: 10.1200/JCO.2014.59.0018. Epub 2016 Sep 30.


The phosphoinositide 3-kinase (PI3K) pathway plays an integral role in many cellular processes and is frequently altered in cancer, contributing to tumor growth and survival. Small molecule inhibitors have been developed that target the three major nodes of this pathway: PI3K, AKT, and mammalian target of rapamycin. However, because oncogenic PI3K pathway activation is achieved in diverse, potentially redundant ways, the clinical efficacy of these inhibitors as monotherapies has, so far, been limited, despite demonstrating promising preclinical activity. Moreover, pathway activation is associated with resistance to other therapies; thus, in combination, PI3K pathway inhibitors could restore therapeutic sensitivity to these agents. To maximize therapeutic benefit, drug combinations and schedules must be explored to identify those with the highest efficacy and lowest toxicity overlap. In addition, defining appropriate patient subpopulations, for both monotherapy and drug combinations, will be important. However, identifying predictive biomarkers remains a challenge.

Publication types

  • Review

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Enzyme Inhibitors / administration & dosage
  • Humans
  • Molecular Targeted Therapy / methods
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / drug effects*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / metabolism
  • Treatment Outcome


  • Enzyme Inhibitors
  • Phosphoinositide-3 Kinase Inhibitors
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt