Targeting the PI3K/Akt/mTOR Pathway: Effective Combinations and Clinical Considerations

Drug Resist Updat. Feb-Apr 2008;11(1-2):32-50. doi: 10.1016/j.drup.2007.11.003. Epub 2007 Dec 31.

Abstract

The PI3K/Akt/mTOR pathway is a prototypic survival pathway that is constitutively activated in many types of cancer. Mechanisms for pathway activation include loss of tumor suppressor PTEN function, amplification or mutation of PI3K, amplification or mutation of Akt, activation of growth factor receptors, and exposure to carcinogens. Once activated, signaling through Akt can be propagated to a diverse array of substrates, including mTOR, a key regulator of protein translation. This pathway is an attractive therapeutic target in cancer because it serves as a convergence point for many growth stimuli, and through its downstream substrates, controls cellular processes that contribute to the initiation and maintenance of cancer. Moreover, activation of the Akt/mTOR pathway confers resistance to many types of cancer therapy, and is a poor prognostic factor for many types of cancers. This review will provide an update on the clinical progress of various agents that target the pathway, such as the Akt inhibitors perifosine and PX-866 and mTOR inhibitors (rapamycin, CCI-779, RAD-001) and discuss strategies to combine these pathway inhibitors with conventional chemotherapy, radiotherapy, as well as newer targeted agents. We will also discuss how the complex regulation of the PI3K/Akt/mTOR pathway poses practical issues concerning the design of clinical trials, potential toxicities and criteria for patient selection.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols* / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols* / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols* / therapeutic use
  • Clinical Trials as Topic
  • Combined Modality Therapy
  • Humans
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Signal Transduction / drug effects
  • Substrate Specificity
  • TOR Serine-Threonine Kinases
  • Treatment Outcome

Substances

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