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.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Alleles
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Animals
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Calcium Channels / genetics
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Cell Line, Tumor
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Drosophila / genetics
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Drosophila / metabolism
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Drug Screening Assays, Antitumor
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Enzyme Inhibitors / pharmacology
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Female
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G1 Phase Cell Cycle Checkpoints / genetics
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Gene Library
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High-Throughput Screening Assays
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Humans
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Leukemia / genetics*
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Leukemia / metabolism*
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Mice
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Mice, SCID
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Mutation
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Neoplasm Transplantation
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Receptor, Notch1 / antagonists & inhibitors
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Receptor, Notch1 / genetics*
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Sarcoplasmic Reticulum Calcium-Transporting ATPases / antagonists & inhibitors
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Sarcoplasmic Reticulum Calcium-Transporting ATPases / genetics*
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Signal Transduction / genetics
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Small Molecule Libraries
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Thapsigargin / pharmacology
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Transplantation, Heterologous
Substances
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Calcium Channels
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Enzyme Inhibitors
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Notch1 protein, mouse
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Receptor, Notch1
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Small Molecule Libraries
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Thapsigargin
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Sarcoplasmic Reticulum Calcium-Transporting ATPases