The cautionary tale of side effects of chronic Notch1 inhibition.
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.
Department of Cancer Biology, University of Pennsylvania School of Medicine, Abramson Family Cancer Research Institute, 311 BRB, 421 Curie Boulevard, Philadelphia, Pennsylvania 19106, USA. sryeom@upenn.edu
Sandra W
SW
Ryeom
D000818:Animals; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000502:physiology*; D019043:Vascular Neoplasms / Q000378:metabolism* / Q000473:pathology
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051881:Receptor, Notch1; C064045:delta protein
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20484026
Nat Immunol. 2004 Mar;5(3):247-53
14985712
Biochem Pharmacol. 2010 Sep 1;80(5):690-701
20361945
Nature. 2006 Dec 21;444(7122):1083-7
17183323
Nat Rev Cancer. 2003 Oct;3(10):756-67
14570040
Nature. 2010 Apr 15;464(7291):1052-7
20393564
Nature. 2005 Jun 16;435(7044):959-63
15959515
Cancer Res. 2007 Mar 1;67(5):1879-82
17332312
Nature. 2010 Feb 11;463(7282):E6-7
20147986
Annu Rev Pathol. 2008;3:587-613
18039126
J Clin Invest. 2011 Feb;121(2):800-8
21266774
Cancer. 2010 Dec 15;116(24):5676-85
20737536