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The Biology and Clinical Relevance of the PTEN Tumor Suppressor Pathway

From the Department of Medical Oncology, Dana-Farber Cancer Institute; and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA

Address reprint requests to William R. Sellers, MD, Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 44 Binney St, Boston, MA 02115; e-mail: william_sellers{at}dfci.harvard.edu

Genetic alterations targeting the PTEN tumor suppressor gene are among the most frequently noted somatic mutations in human cancers. Such lesions have been noted in cancers of the prostate and endometrium and in glioblastoma multiforme, among many others. Moreover, germline mutation of PTEN leads to the development of the related hereditary cancer predisposition syndromes, Cowden disease, and Bannayan-Zonana syndrome, wherein breast and thyroid cancer incidence is elevated. The protein product, PTEN, is a lipid phosphatase, the enzymatic activity of which primarily serves to remove phosphate groups from key intracellular phosphoinositide signaling molecules. This activity normally serves to restrict growth and survival signals by limiting activity of the phosphoinositide-3 kinase (PI3K) pathway. Multiple lines of evidence support the notion that this function is critical to the ability of PTEN to maintain cell homeostasis. Indeed, the absence of functional PTEN in cancer cells leads to constitutive activation of downstream components of the PI3K pathway including the Akt and mTOR kinases. In model organisms, inactivation of these kinases can reverse the effects of PTEN loss. These data raise the possibility that drugs targeting these kinases, or PI3K itself, might have significant therapeutic activity in PTEN-null cancers. Akt kinase inhibitors are still in development; however, as a first test of this hypothesis, phase I and phase II trials of inhibitors of mTOR, namely, rapamycin and rapamycin analogs are underway.

Supported by National Cancer Institute grants RO1CA85912, PO1CA89021, U01CA84995, and P50CA09038; CaP CURE (W.R.S.); the Damon Runyon Cancer Research Foundation; the Dana-Farber/Novartis Drug Discovery Program; and the Department of Defense Prostate Cancer Research Program grant DAMD17-02-1-0048 (I.S.).

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

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