title: 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: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors: Giovanni
authors: G
authors: Roti
authors: Anne
authors: A
authors: Carlton
authors: Kenneth N
authors: KN
authors: Ross
authors: Michele
authors: M
authors: Markstein
authors: Kostandin
authors: K
authors: Pajcini
authors: Angela H
authors: AH
authors: Su
authors: Norbert
authors: N
authors: Perrimon
authors: Warren S
authors: WS
authors: Pear
authors: Andrew L
authors: AL
authors: Kung
authors: Stephen C
authors: SC
authors: Blacklow
authors: Jon C
authors: JC
authors: Aster
authors: Kimberly
authors: K
authors: Stegmaier
mesh_terms: D000483:Alleles; D000818:Animals; D015220:Calcium Channels / Q000235:genetics; D045744:Cell Line, Tumor; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics; D015723:Gene Library; D057166:High-Throughput Screening Assays; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D009368:Neoplasm Transplantation; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D054852:Small Molecule Libraries; D019284:Thapsigargin / Q000494:pharmacology; D014183:Transplantation, Heterologous
chemical_list: D015220:Calcium Channels; D004791:Enzyme Inhibitors; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D054852:Small Molecule Libraries; D019284:Thapsigargin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases