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

Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations.

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1
Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20889, United States.

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.

PMID:
18166498
PMCID:
PMC2442829
DOI:
10.1016/j.drup.2007.11.003
[Indexed for MEDLINE]
Free PMC Article
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