Key Points
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There are several therapeutics that target the PI3K–Akt pathway in clinical development for the treatment of cancer. These include dual PI3K–mTOR inhibitors, PI3K inhibitors, Akt inhibitors and mTOR complex catalytic site inhibitors.
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The PI3K–Akt pathway is inappropriately activated in many cancers. The pathway is activated by receptor tyrosine kinases, as well as by the genetic mutation and amplification of key pathway components.
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The most effective type of therapeutic used to inhibit this pathway is likely to depend on the particular mechanism of PI3K–Akt activation in a cancer.
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So far, preclinical data suggest that PI3K–Akt pathway inhibitors might have single-agent activity in breast cancers with ERBB2 amplifications or PIK3CA mutations. These drugs might also be effective in overcoming acquired resistance to therapies that target receptor tyrosine kinases (such as acquired resistance to trastuzumab or erlotinib).
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Drugs targeting the PI3K–Akt pathway might most effectively treat cancers when they are used in combination with other targeted therapies, such as MEK inhibitors.
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Effective clinical development will centre on determining why these compounds fail when they do. It will be important to determine whether a drug could not effectively downregulate PI3K–Akt signalling or if effective inhibition of the pathway was not sufficient to produce a clinical response.
Abstract
There are ample genetic and laboratory studies that suggest the PI3K–Akt pathway is vital to the growth and survival of cancer cells. Inhibitors targeting this pathway are entering the clinic at a rapid pace. In this Review, the therapeutic potential of drugs targeting PI3K–Akt signalling for the treatment of cancer is discussed. I focus on the advantages and drawbacks of different treatment strategies for targeting this pathway, the cancers that might respond best to these therapies and the challenges and limitations that confront their clinical development.
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Acknowledgements
0I am grateful to L. Cantley and the members of his laboratory for discussions and insights regarding PI3K signalling. I thank my laboratory, P. Jänne's laboratory and J. Settleman's laboratory for discussions regarding oncogene addiction and resistance to targeted therapies. I apologize to the many authors whose work I could not cite directly because of space limitations. This work was supported by the National Institutes of Health.
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Competing interests
Jeffrey Engelman is a consultant for Novartis, Millennium, Schering–Plough and AVEO, and on the scientific advisory board for Hoffman–La Roche.
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DATABASES
National Cancer Institute Drug Dictionary
[18F] 2-fluoro-2-deoxy-D-glucose
FURTHER INFORMATION
Glossary
- Oncogene addiction
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A cellular condition in which a cancer cell requires the activity of a specific oncogene or cellular process for growth and survival. Inhibition of that specific function leads to cell death.
- Vasculogenesis
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The process of blood vessel formation that occurs by the production of endothelial cells.
- Pharmacodynamic
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The study of the biochemical and physiological effects of drugs on the body, the mechanisms of drug action and the relationship between drug concentration and effect.
- RECIST
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RECIST (Response Evaluation Criteria In Solid Tumours) is a set of published rules that define when cancer patients improve, stay the same or progress during treatments.
- Neoadjuvant
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A cancer therapy that is delivered before a surgical procedure.
- Insulin resistance
-
The condition in which normal amounts of insulin are inadequate for the production of a normal insulin response from fat, muscle and liver cells.
- Hyperinsulinaemia
-
Increased insulin levels in the blood. This is often observed when a person becomes insulin resistant as their body attempts to control blood glucose levels.
- Hyperglycaemia
-
Increased levels of glucose in the blood. This usually occurs in adult-onset diabetes because insulin-sensitive tissues become less responsive to insulin.
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Engelman, J. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 9, 550–562 (2009). https://doi.org/10.1038/nrc2664
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DOI: https://doi.org/10.1038/nrc2664
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