Complementary Genomic Screens Identify SERCA as a Therapeutic Target in NOTCH1 Mutated Cancer

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...

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Bibliographic Details
Published in:Cancer cell 2013-03, Vol.23 (3), p.390-405
Main Authors: Roti, Giovanni, Carlton, Anne, Ross, Kenneth N., Markstein, Michele, Pajcini, Kostandin, Su, Angela H., Perrimon, Norbert, Pear, Warren S., Kung, Andrew L., Blacklow, Stephen C., Aster, Jon C., Stegmaier, Kimberly
Format: Article
Language:English
Subjects:
Alleles
Animals
Calcium Channels - genetics
Cell Line, Tumor
Drosophila - genetics
Drosophila - metabolism
Drug Screening Assays, Antitumor
Enzyme Inhibitors - pharmacology
Female
G1 Phase Cell Cycle Checkpoints - genetics
Gene Library
High-Throughput Screening Assays
Humans
Leukemia - genetics
Leukemia - metabolism
Mice
Mice, SCID
Mutation
Neoplasm Transplantation
Receptor, Notch1 - antagonists & inhibitors
Receptor, Notch1 - genetics
Sarcoplasmic Reticulum Calcium-Transporting ATPases - antagonists & inhibitors
Sarcoplasmic Reticulum Calcium-Transporting ATPases - genetics
Signal Transduction - genetics
Small Molecule Libraries
Thapsigargin - pharmacology
Transplantation, Heterologous
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Summary: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. ► Intersecting high-throughput screens identify SERCA inhibition to modulate Notch1 ► A small-molecule SERCA inhibitor has on-target antileukemia activity in vitro ► A SERCA inhibitor has on-target antileukemia activity in T-ALL mouse models ► SERCA inhibition preferentially impairs the maturation of mutated Notch1 receptors
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccr.2013.01.015