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Cancer Cell. 2013 Mar 18;23(3):390-405. doi: 10.1016/j.ccr.2013.01.015. Epub 2013 Feb 21.

Complementary genomic screens identify SERCA as a therapeutic target in NOTCH1 mutated cancer.

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1
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Abstract

Notch1 is a rational therapeutic target in several human cancers, but as a transcriptional regulator, it poses a drug discovery challenge. To identify Notch1 modulators, we performed two cell-based, high-throughput screens for small-molecule inhibitors and cDNA enhancers of a NOTCH1 allele bearing a leukemia-associated mutation. Sarco/endoplasmic reticulum calcium ATPase (SERCA) channels emerged at the intersection of these complementary screens. SERCA inhibition preferentially impairs the maturation and activity of mutated Notch1 receptors and induces a G0/G1 arrest in NOTCH1-mutated human leukemia cells. A small-molecule SERCA inhibitor has on-target activity in two mouse models of human leukemia and interferes with Notch signaling in Drosophila. These studies "credential" SERCA as a therapeutic target in cancers associated with NOTCH1 mutations.

PMID:
23434461
PMCID:
PMC3709972
DOI:
10.1016/j.ccr.2013.01.015
[Indexed for MEDLINE]
Free PMC Article
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