Roti, G., Carlton, A., Ross, K.N., Markstein, M., Pajcini, K., Su, A.H., Perrimon, N., Pear, W.S., Kung, A.L., Blacklow, S.C., Aster, J.C., Stegmaier, K. (2013). Complementary Genomic Screens Identify SERCA as a Therapeutic Target in NOTCH1 Mutated Cancer.  Cancer Cell 23(3): 390--405.

FBrf0221121

Research paper

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.

PMC3709972 (PMC) (EuropePMC)