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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

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