Complementary Genomic Screens Identify SERCA as a Therapeutic Target in NOTCH1 Mutated Cancer
Menée in vitro et à l'aide de modèles murins, cette étude suggère l'intérêt de cibler la protéine SERCA pour le traitement de leucémies présentant des mutations du gène NOTCH1
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. º Intersecting high-throughput screens identify SERCA inhibition to modulate Notch1 º A small-molecule SERCA inhibitor has on-target antileukemia activity in vitro º A SERCA inhibitor has on-target antileukemia activity in T-ALL mouse models º SERCA inhibition preferentially impairs the maturation of mutated Notch1 receptors