Originally published as JCO Early Release 10.1200/JCO.2008.20.0766 on March 30 2009

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Targeting the mTOR Signaling Network for Cancer Therapy

From the Departments of Surgical Oncology and Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX.

Corresponding author: Funda Meric-Bernstam, MD, Department of Surgical Oncology, Unit 444, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030; e-mail: fmeric{at}mdanderson.org.

The serine-threonine kinase mammalian target of rapamycin (mTOR) plays a major role in the regulation of protein translation, cell growth, and metabolism. Alterations of the mTOR signaling pathway are common in cancer, and thus mTOR is being actively pursued as a therapeutic target. Rapamycin and its analogs (rapalogs) have proven effective as anticancer agents in a broad range of preclinical models. Clinical trials using rapalogs have demonstrated important clinical benefits in several cancer types; however, objective response rates achieved with single-agent therapy have been modest. Rapalogs may be more effective in combination with other anticancer agents, including chemotherapy and targeted therapies. It is increasingly apparent that the mTOR signaling network is quite complex, and rapamycin treatment leads to different signaling responses in different cell types. A better understanding of mTOR signaling, the mechanism of action of rapamycin, and the identification of biomarkers of response will lead to more optimal targeting of this pathway for cancer therapy.

The authors' laboratory research is funded by National Institutes of Health (NIH) Grant No. NIH1 R01 CA112199 (F.M.-B.), American Institute of Cancer Research (F.M.-B.), Grant No. NIH K23 CA121994 (A.M.G.-A.), ASCO Career Development Award (A.M.G.-A.), and the Cancer Center Core Grant No. CA16672 from The University of Texas M. D. Anderson Cancer Center.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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