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Article
Complementary genomic screens identify SERCA as a therapeutic target in NOTCH1 mutated cancer
Cancer Cell (2013)
  • G. Roti
  • A. Carlton
  • KN. Ross
  • Michele Markstein, University of Massachusetts - Amherst
  • K. Pajcini
  • A. H. Su
  • N. Perrimon
  • W. S. Pear
  • A. L. Kung
  • S. C. Blacklow
  • J. C. Aster
  • K. Stegmaier
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.

Keywords
  • Notch inhibitors,
  • Screening,
  • Intestinal Stem Cells
Publication Date
2013
Citation Information
G. Roti, A. Carlton, KN. Ross, Michele Markstein, et al.. "Complementary genomic screens identify SERCA as a therapeutic target in NOTCH1 mutated cancer" Cancer Cell (2013)
Available at: http://works.bepress.com/michele_markstein/10/