Complementary Genomic Screens Identify SERCA as a Therapeutic Target in NOTCH1 Mutated Cancer

SummaryNotch1 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.

► Intersecting high-throughput screens identify SERCA inhibition to modulate Notch1
► A small-molecule SERCA inhibitor has on-target antileukemia activity in vitro
► A SERCA inhibitor has on-target antileukemia activity in T-ALL mouse models
► SERCA inhibition preferentially impairs the maturation of mutated Notch1 receptors