Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 7-Day Trial for You or Your Team.

Learn More →

Exploiting the PI3K/AKT Pathway for Cancer Drug Discovery

Exploiting the PI3K/AKT Pathway for Cancer Drug Discovery The phosphatidylinositol-3-kinase (PI3K) pathway plays a crucial role in cell growth and survival and is activated in various cancers. Multiple components of the pathway are frequently targeted by amplification, mutation, and, less commonly, translocation in neoplasia; there is also crosstalk with the p53 and retinoblastoma pathways to comprise a signalling network that promotes tumour initiation and progression. Despite major interest in this pathway for cancer drug discovery, no drugs have yet been approved that act specifically against PI3K or its downstream regulator, AKT. However, several drugs that were developed for other purposes either directly or indirectly target PI3K signaling, such as the rapamycin analogs, the ether lipids perifosine and miltefosine, and inhibitors of the epidermal growth factor receptor (EGFR), HER2, c-kit, platelet-derived growth factor receptor (PDGFR) and bcr–abl. Because of the crucial role of the PI3K pathway in normal cell growth and in the cellular response to stress, the main challenge to developing PI3K pathway-targeted drugs is to identify inhibitors with a usable therapeutic index. It is likely that PI3K inhibitors will need to be used in combination with other drugs that induce cell stress, such as other signaling inhibitors, radio- and chemotherapy. Points at which therapeutic intervention might be useful in the PI3K pathway include PI3K itself, the downstream regulator AKT, although toxicity has thus far precluded use of specific inhibitors of this crucial signaling node, and other downstream components such as mTOR, integrin-linked kinase (ILK), phosphoinositide-dependent kinase-1 (PDK-1), p70S6 kinase, and Forkhead/FOXO1. As with other molecularly targeted agents such as imatinib mesylate (Gleevec) and trastuzumab (Herceptin), the success of PI3K inhibitors will probably depend on the selection of cancer patients likely to be responders based on genomic aberrations. The co-development of molecular markers determining early response will allow triage of non-responders to other therapies and thereby increase the utility of targeted agents. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nature Reviews Drug Discovery Springer Journals

Exploiting the PI3K/AKT Pathway for Cancer Drug Discovery

Download PDF
17 pages

Loading next page...
 
/lp/springer-journals/exploiting-the-pi3k-akt-pathway-for-cancer-drug-discovery-1nWeGxopPS

References (203)

Publisher
Springer Journals
Copyright
Copyright © 2005 by Nature Publishing Group
Subject
Biomedicine; Biomedicine, general; Pharmacology/Toxicology; Biotechnology; Medicinal Chemistry; Molecular Medicine; Cancer Research
ISSN
1474-1776
eISSN
1474-1784
DOI
10.1038/nrd1902
Publisher site
See Article on Publisher Site

Abstract

The phosphatidylinositol-3-kinase (PI3K) pathway plays a crucial role in cell growth and survival and is activated in various cancers. Multiple components of the pathway are frequently targeted by amplification, mutation, and, less commonly, translocation in neoplasia; there is also crosstalk with the p53 and retinoblastoma pathways to comprise a signalling network that promotes tumour initiation and progression. Despite major interest in this pathway for cancer drug discovery, no drugs have yet been approved that act specifically against PI3K or its downstream regulator, AKT. However, several drugs that were developed for other purposes either directly or indirectly target PI3K signaling, such as the rapamycin analogs, the ether lipids perifosine and miltefosine, and inhibitors of the epidermal growth factor receptor (EGFR), HER2, c-kit, platelet-derived growth factor receptor (PDGFR) and bcr–abl. Because of the crucial role of the PI3K pathway in normal cell growth and in the cellular response to stress, the main challenge to developing PI3K pathway-targeted drugs is to identify inhibitors with a usable therapeutic index. It is likely that PI3K inhibitors will need to be used in combination with other drugs that induce cell stress, such as other signaling inhibitors, radio- and chemotherapy. Points at which therapeutic intervention might be useful in the PI3K pathway include PI3K itself, the downstream regulator AKT, although toxicity has thus far precluded use of specific inhibitors of this crucial signaling node, and other downstream components such as mTOR, integrin-linked kinase (ILK), phosphoinositide-dependent kinase-1 (PDK-1), p70S6 kinase, and Forkhead/FOXO1. As with other molecularly targeted agents such as imatinib mesylate (Gleevec) and trastuzumab (Herceptin), the success of PI3K inhibitors will probably depend on the selection of cancer patients likely to be responders based on genomic aberrations. The co-development of molecular markers determining early response will allow triage of non-responders to other therapies and thereby increase the utility of targeted agents.

Journal

Nature Reviews Drug Discovery – Springer Journals

Published: Dec 1, 2005

There are no references for this article.