Key Points
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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.
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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.
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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.
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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.
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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.
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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.
Abstract
Evolving studies with several different targeted therapeutic agents are demonstrating that patients with genomic alterations of the target, including amplification, translocation and mutation, are more likely to respond to the therapy. Recent studies indicate that numerous components of the phosphatidylinositol-3-kinase (PI3K)/AKT pathway are targeted by amplification, mutation and translocation more frequently than any other pathway in cancer patients, with resultant activation of the pathway. This warrants exploiting the PI3K/AKT pathway for cancer drug discovery.
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Acknowledgements
The authors' research is supported by National Institutes of Health (NIH) grants to G.B.M. as well as by a Department Of Defence grant to P.T.R., and Aventis Pharmaceutical M.D. Anderson fellowship award to B.T.H., and a training fellowship from the Keck Centern Pharmacoinformatic Training Program at the Gulf Coast Consortia (NIH grant) to D.L.S.
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G.B.M. has financial relationships with QLT Inc., Semafore Pharmaceuticals, Eli Lilly & Co., Keryx Biopharmaceuticals and Abbott Laboratories.
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DATABASES
Entrez Gene
OMIM
dermatofibrosarcoma protuberans
FURTHER INFORMATION
Nucleic Acids Reaseach Database List
The Sanger Institute Catalogues of Somatic Mutations in Cancer
Glossary
- HAMARTOMAS
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Abnormal growth of mature normal cells and tissues in an organ composed of identical elements.
- REVERSE PHASE PROTEIN ARRAY
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An array that immobilizes the whole repertoire of patient proteins that represent the state of individual tissue cell populations undergoing disease transitions.
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Hennessy, B., Smith, D., Ram, P. et al. Exploiting the PI3K/AKT Pathway for Cancer Drug Discovery. Nat Rev Drug Discov 4, 988–1004 (2005). https://doi.org/10.1038/nrd1902
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DOI: https://doi.org/10.1038/nrd1902
