PI3K/Akt/mTOR pathway as a target for cancer therapy

Abstract

The PI3K/Akt/mTOR pathway regulates several normal cellular functions that are also critical for tumorigenesis, including cellular proliferation, growth, survival and mobility. Components of this pathway are frequently abnormal in a variety of tumors, making them an attractive target for anti-cancer therapy. Inhibition of mTOR in patients with cancer became more feasible after the development of rapamycin analogs with improved pharmacologic properties. The promising activity of these agents in early clinical trials has led to the development of ongoing phase III trials in renal cell carcinoma and breast cancer. Future studies are needed to identify the patients most likely to benefit from this form of therapy, and to define its role in combination with chemotherapy, hormones and growth factor inhibitors.

Glibenclamide activates translation in rat pancreatic beta cells through calcium-dependent mTOR, PKA and MEK signalling pathways

“…As in other cell types and experimental conditions, the glibenclamide activation of mTOR can be explained by the rise in intracellular calcium [31,32], which acts through phosphorylation of PKB [33] and activation of PKA [8] or an as yet undefined intermediate. Glibenclamide induced phosphorylation of PKB, a well-known upstream kinase of mTOR [10,34,35]; this effect was not influenced by rapamycin, but was completely abolished by verapamil and the PKA inhibitor. It was, however, noticed that the PKA inhibitor only partially suppressed phosphorylation of 4E-BP1 and rpS6, while rapamycin and verapamil caused complete suppression.…”

Regulatory Effects of Mammalian Target of Rapamycin-activated Pathways in Type I and II Interferon Signaling

“…It is generally established and accepted that activation of the mTOR pathway mediates progrowth and survival signals (35,36,41). Moreover, mTOR has been implicated in the pathophysiology of several malignancies, and its pharmacological targeting is currently under extensive investigation for the treatment of various cancers (34,41,(52)(53)(54)(55)(56). The fact that the same pathway can selectively mediate signals for the biological effects of IFNs, cytokines, with antitumor and antiviral properties suggests the existence of an IFN-regulated specific mechanism that transiently diverts mTOR and its effectors from the transmission of mitogenic signals and redirects cap-dependent translation to proteins that exhibit opposing biological effects.…”

A gene transcription signature of the Akt/mTOR pathway in clinical breast tumors

“…The pathway is commonly deregulated in cancer (Morgensztern and McLeod, 2005;Shaw and Cantley, 2006), and clinical trials, including trials at the Phase III stage for breast cancer, are currently underway to test the efficacy of treatment using mTOR antagonists. Although preclinical and early clinical results have been encouraging, there is a real need for biomarkers for selecting those patients who may benefit most from anti-mTOR therapy (Morgensztern and McLeod, 2005;Johnston, 2006).…”

“…The pathway is commonly deregulated in cancer (Morgensztern and McLeod, 2005;Shaw and Cantley, 2006), and clinical trials, including trials at the Phase III stage for breast cancer, are currently underway to test the efficacy of treatment using mTOR antagonists. Although preclinical and early clinical results have been encouraging, there is a real need for biomarkers for selecting those patients who may benefit most from anti-mTOR therapy (Morgensztern and McLeod, 2005;Johnston, 2006). Recent studies have defined mRNA expression patterns, or 'signatures', of deregulation of specific pathways -including Myc, Ras, cyclin D1, b-catenin, HER2/neu, epidermal growth factor receptor and mitogen-activated protein kinasein human cancer (Lamb et al, 2003;Sweet-Cordero et al, 2005;Bild et al, 2006;Creighton et al, 2006a, b).…”