Roti, GiovanniCarlton, AnneRoss, KennethMarkstein, MichelePajcini, KostandinSu, Angela H.Perrimon, NorbertPear, Warren S.Kung, Andrew L.Blacklow, StephenAster, JonStegmaier, Kimberly2022-07-152013-03-18Roti, Giovanni, Anne Carlton, Kenneth Ross, Michele Markstein, Kostandin Pajcini, Angela H. Su, Norbert Perrimon et al. "Complementary Genomic Screens Identify SERCA as a Therapeutic Target in NOTCH1 Mutated Cancer." Cancer Cell 23, no. 3 (2013): 390-405. DOI: 10.1016/j.ccr.2013.01.0151535-61081878-3686https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37372613Notch1 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. SERCA calcium 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.en-USResearch Subject Categories::NATURAL SCIENCES::Biology::Cell and molecular biologyResearch Subject Categories::MEDICINE::Morphology, cell biology, pathology::Morphology::Tumour biologyJournal Article2022-07-1510.1016/j.ccr.2013.01.015