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Context Is Key: Differential PI3K Signaling And Consequences For Targeted Therapy

Date:
July 14, 2009
Source:
Cold Spring Harbor Laboratory
Summary:
Scientists have made a surprising discovery of cell-type specificity of PI3K signaling in the mammalian brain. This finding highlights the complexity of this clinically significant cell signaling pathway, and its relevance to the design of small molecule PI3K pathway inhibitors, to both maximize efficacy and minimize side effects.
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In the July 15th issue of Genes & Development, Dr. Suzanne Baker (St. Jude Children's Research Hospital) and colleagues report on their surprising discovery of cell-type specificity of PI3K signaling in the mammalian brain. This finding highlights the complexity of this clinically significant cell signaling pathway, and its relevance to the design of small molecule PI3K pathway inhibitors, to both maximize efficacy and minimize side effects.

The PI3K pathway is an intricate signaling cascade that regulates cell survival and growth under normal, as well as pathological conditions. In fact, the PI3K pathway is mutated in more cancer patients than any other. The signaling network is balanced by the PTEN tumor suppressor protein.

PTEN (Phosphatase and Tensin Homologue Deleted from Chromosome-10) is recognized as one of the most frequently mutated tumor suppressors in human cancer, and has also been associated with neurological diseases like autism. It functions primarily as a phosphatase (phosphate-group-cleaving enzyme) to antagonize PI3K signaling by dephosphorylating PIP3, the lipid second messenger that signals activation of the PI3K signaling cascade. Loss of PTEN results in the upregulation of PI3K signaling, through the increased phosphorylation of PI3K effectors such as the molecule, AKT. Thus, the PTEN/PI3K/AKT pathway represents an important target for drug discovery.

To study the role of the PI3K downstream effector molecule, PDK1, in mediating the effects of PTEN loss, Dr. Baker and colleagues generated a novel transgenic mouse strain deficient in both PDK1 and PTEN specifically in the brain. The researchers found that while some of the characteristic brain abnormalities arising from PTEN loss are corrected by the concomitant deletion of PDK1, others are not: Most notably, PDK1 did not rescue the migration defects associated with PTEN loss in neurons. PDK1-independent abnormalities in the brains of PTEN-deficient mice suggests that additional, alternate downstream effectors of the PI3K signal exist.

This finding underscores the consideration that, as Dr. Baker explains, "inhibitors that block downstream effectors in PI3K signaling may not correct all of the defects caused by loss of PTEN function."

Dr. Baker's team also observed differential feedback regulation of the PI3K pathway in different CNS cell types. Clinical evidence has shown that some human tumors achieve chemoresistance through the increased phosphorylation of the PI3K downstream component, AKT. Quite surprisingly, Dr. Baker and colleagues found that PDK1 deletion caused a selective, dramatic increase in the phosphorylation of AKT in glial cells, but not neurons, indicating unanticipated cell-type specificity in PI3K feedback regulation in the brain.

Further research will be needed to determine if PDK1, itself, represents a useful therapeutic target. However, this example of a cell type-specific response to PDK1 deletion supports the notion of personalized cancer treatment, in so far as emphasizing the relevance of tumor cell of origin and genotype to help predict which patients will respond positively to specific PI3K inhibitors.

Dr. Baker emphasizes that, likewise, "There may be profound differences in the effects of inhibitors on different types of normal cells, which could be relevant in terms of side effects induced by systemic treatment with a pathway inhibitor."


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Materials provided by Cold Spring Harbor Laboratory. Note: Content may be edited for style and length.


Cite This Page:

Cold Spring Harbor Laboratory. "Context Is Key: Differential PI3K Signaling And Consequences For Targeted Therapy." ScienceDaily. ScienceDaily, 14 July 2009. <www.sciencedaily.com/releases/2009/07/090714191836.htm>.
Cold Spring Harbor Laboratory. (2009, July 14). Context Is Key: Differential PI3K Signaling And Consequences For Targeted Therapy. ScienceDaily. Retrieved May 23, 2017 from www.sciencedaily.com/releases/2009/07/090714191836.htm
Cold Spring Harbor Laboratory. "Context Is Key: Differential PI3K Signaling And Consequences For Targeted Therapy." ScienceDaily. www.sciencedaily.com/releases/2009/07/090714191836.htm (accessed May 23, 2017).

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