Xuerong Wang1, Shi-Yong Sun. 1. Emory University School of Medicine, Winship Cancer Institute, Department of Hematology, Atlanta, GA 30322, USA.
Abstract
BACKGROUND: The mammalian target of rapamycin (mTOR) has emerged as an attractive cancer therapeutic target. Accordingly, several mTOR inhibitors (e.g., rapamycin and its analogs; rapalogs) are currently being tested in many cancer clinical trials. Despite the encouraging results showing that some rapalogs improved overall survival among patients with metastatic renal-cell carcinoma, the single-agent activity of rapalogs in most other tumor-types has been modest, at best. OBJECTIVE: To review the current understanding of the mTOR axis and discuss potential strategies to enhance mTOR-targeted cancer therapy. METHODS: Preclinical and clinical data in peer-reviewed reports on the novel biological and therapeutic parts of the mTOR axis are discussed. CONCLUSION: The mTOR axis involves complex regulatory networks. Inhibition of the mTOR axis with a rapalog induces feedback activation of several survival signaling pathways such as Akt activation, which, in turn, blunt rapalogs' anticancer efficacy. Thus, blockage or prevention of the activation of these survival signaling pathways may enhance mTOR-targeted cancer therapy.
BACKGROUND: The mammalian target of rapamycin (mTOR) has emerged as an attractive cancer therapeutic target. Accordingly, several mTOR inhibitors (e.g., rapamycin and its analogs; rapalogs) are currently being tested in many cancer clinical trials. Despite the encouraging results showing that some rapalogs improved overall survival among patients with metastatic renal-cell carcinoma, the single-agent activity of rapalogs in most other tumor-types has been modest, at best. OBJECTIVE: To review the current understanding of the mTOR axis and discuss potential strategies to enhance mTOR-targeted cancer therapy. METHODS: Preclinical and clinical data in peer-reviewed reports on the novel biological and therapeutic parts of the mTOR axis are discussed. CONCLUSION: The mTOR axis involves complex regulatory networks. Inhibition of the mTOR axis with a rapalog induces feedback activation of several survival signaling pathways such as Akt activation, which, in turn, blunt rapalogs' anticancer efficacy. Thus, blockage or prevention of the activation of these survival signaling pathways may enhance mTOR-targeted cancer therapy.
Authors: David A Guertin; Deanna M Stevens; Maki Saitoh; Stephanie Kinkel; Katherine Crosby; Joon-Ho Sheen; David J Mullholland; Mark A Magnuson; Hong Wu; David M Sabatini Journal: Cancer Cell Date: 2009-02-03 Impact factor: 31.743
Authors: Roeland F de Wilde; Barish H Edil; Ralph H Hruban; Anirban Maitra Journal: Nat Rev Gastroenterol Hepatol Date: 2012-02-07 Impact factor: 46.802