Mechanistic target of rapamycin (mTOR) is the kinase subunit of two structurally and functionally distinct large multiprotein complexes, referred to as mTOR complex 1 (mTORC1) and mTORC2. mTORC1 and mTORC2 play key physiological roles as they control anabolic and catabolic processes in response to external cues in a variety of tissues and organs. However, mTORC1 and mTORC2 activities are deregulated in widespread human diseases, including cancer. Cancer cells take advantage of mTOR oncogenic signaling to drive their proliferation, survival, metabolic transformation, and metastatic potential. Therefore, mTOR lends itself very well as a therapeutic target for innovative cancer treatment. mTOR was initially identified as the target of the antibiotic rapamycin that displayed remarkable antitumor activity in vitro. Promising preclinical studies using rapamycin and its derivatives (rapalogs) demonstrated efficacy in many human cancer types, hence supporting the launch of numerous clinical trials aimed to evaluate the real effectiveness of mTOR-targeted therapies. However, rapamycin and rapalogs have shown very limited activity in most clinical contexts, also when combined with other drugs. Thus, novel classes of mTOR inhibitors with a stronger antineoplastic potency have been developed. Nevertheless, emerging clinical data suggest that also these novel mTOR-targeting drugs may have a weak antitumor activity. Here, we summarize the current status of available mTOR inhibitors and highlight the most relevant results from both preclinical and clinical studies that have provided valuable insights into both their efficacy and failure.
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March 2018
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CD31 immunofluorescence staining of a mesenteric window taken from a rat with liver cirrhosis. In Clinical Science volume 132, Issue 6, Huang et al. use CD31 immunofluorescence staining to show an increased density of the vascular network in the mesenteric window of rats with bile duct ligation-induced liver cirrhosis. Vascular network density is usually low in non-cirrhotic condition, indicating that mesenteric angiogenesis takes place in liver cirrhosis; for details see pages 669–683.
Review Article|
March 09 2018
Drug discovery targeting the mTOR pathway
Alberto M. Martelli;
1Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy
Correspondence: Alberto M. Martelli ([email protected]) or James A. McCubrey ([email protected])
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Francesca Buontempo;
Francesca Buontempo
1Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy
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James A. McCubrey
2Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27858, U.S.A.
Correspondence: Alberto M. Martelli ([email protected]) or James A. McCubrey ([email protected])
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Publisher: Portland Press Ltd
Received:
January 22 2018
Revision Received:
February 09 2018
Accepted:
February 13 2018
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2018
Clin Sci (Lond) (2018) 132 (5): 543–568.
Article history
Received:
January 22 2018
Revision Received:
February 09 2018
Accepted:
February 13 2018
Citation
Alberto M. Martelli, Francesca Buontempo, James A. McCubrey; Drug discovery targeting the mTOR pathway. Clin Sci (Lond) 15 March 2018; 132 (5): 543–568. doi: https://doi.org/10.1042/CS20171158
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