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The cautionary tale of side effects of chronic Notch1 inhibition
Sandra W. Ryeom
Sandra W. Ryeom
Published January 25, 2011
Citation Information: J Clin Invest. 2011;121(2):508-509. https://doi.org/10.1172/JCI45976.
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Commentary

The cautionary tale of side effects of chronic Notch1 inhibition

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Abstract

Aberrant Notch1 signaling is implicated in several types of cancer. Therefore, Notch signaling pathways are important anticancer targets. Pan–Notch receptor inhibition is associated with numerous complications; thus, selective Notch receptor inhibition has been pursued. Studies have shown minimal side effects with short-term blockade of either Notch1 or its ligand Delta-like 4, but long-term side effects were not investigated. In this issue of the JCI, Liu et al. use mouse models to demonstrate the consequence of long-term Notch1 inhibition. They present evidence that chronic Notch1 inhibition leads to vascular tumors in the liver and decreased survival, which suggests that Notch1 therapies should be reevaluated.

Authors

Sandra W. Ryeom

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Figure 1

Notch receptor inhibition by various mechanisms.

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Notch receptor inhibition by various mechanisms.
GSIs block γ-secretase ...
GSIs block γ-secretase activity, which is necessary to cleave the Notch intracellular domain. Antibodies that bind to Notch ligands such as DLL4 prevent Notch receptor interaction with its ligand. Inhibitory Notch1-specific antibody prevents protease cleavage of the negative regulatory region of Notch1 after ligand activation.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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