The biology and clinical relevance of the PTEN tumor suppressor pathway

被引:749
作者
Sansal, I
Sellers, WR
机构
[1] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med Oncol,Dana Farber Canc Inst, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA
关键词
D O I
10.1200/jco.2004.02.141
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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. (C) 2004 by American Society of Clinical Oncology.
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页码:2954 / 2963
页数:10
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