@article {824756, title = {Complementary genomic screens identify SERCA as a therapeutic target in NOTCH1 mutated cancer.}, journal = {Cancer Cell}, volume = {23}, number = {3}, year = {2013}, month = {2013 Mar 18}, pages = {390-405}, 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 = {Alleles, Animals, Calcium Channels, Cell Line, Tumor, Drosophila, Drug Screening Assays, Antitumor, Enzyme Inhibitors, Female, G1 Phase Cell Cycle Checkpoints, Gene Library, High-Throughput Screening Assays, Humans, Leukemia, Mice, Mice, SCID, Mutation, Neoplasm Transplantation, Receptor, Notch1, Sarcoplasmic Reticulum Calcium-Transporting ATPases, Signal Transduction, Small Molecule Libraries, Thapsigargin, Transplantation, Heterologous}, issn = {1878-3686}, doi = {10.1016/j.ccr.2013.01.015}, author = {Roti, Giovanni and Carlton, Anne and Ross, Kenneth N and Markstein, Michele and Pajcini, Kostandin and Su, Angela H and Perrimon, Norbert and Pear, Warren S and Kung, Andrew L and Blacklow, Stephen C and Aster, Jon C and Stegmaier, Kimberly} }