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

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.

• Authors: Giovanni Roti, Anne Carlton, Kenneth N Ross, Michele Markstein, Kostandin Pajcini, Angela H Su, Norbert Perrimon, Warren S Pear, Andrew L Kung, Stephen C Blacklow, Jon C Aster, Kimberly Stegmaier
• Journal: Cancer cell (Cancer Cell) Vol. 23 Issue 3 Pg. 390-405 (Mar 18 2013) ISSN: 1878-3686 [Electronic] United States
• PMID: 23434461 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Calcium Channels
• Enzyme Inhibitors
• Notch1 protein, mouse
• Receptor, Notch1
• Small Molecule Libraries
• Thapsigargin
• Sarcoplasmic Reticulum Calcium-Transporting ATPases

Topics

• Alleles
• Animals
• Calcium Channels (genetics)
• Cell Line, Tumor
• Drosophila (genetics, metabolism)
• Drug Screening Assays, Antitumor
• Enzyme Inhibitors (pharmacology)
• Female
• G1 Phase Cell Cycle Checkpoints (genetics)
• Gene Library
• High-Throughput Screening Assays
• Humans
• Leukemia (genetics, metabolism)
• Mice
• Mice, SCID
• Mutation
• Neoplasm Transplantation
• Receptor, Notch1 (antagonists & inhibitors, genetics)
• Sarcoplasmic Reticulum Calcium-Transporting ATPases (antagonists & inhibitors, genetics)
• Signal Transduction (genetics)
• Small Molecule Libraries
• Thapsigargin (pharmacology)
• Transplantation, Heterologous