Mutationally activated NOTCH receptors are found in an increasing number of cancer types with an especially high prevalence in T cell acute lymphoblastic leukemia (T-ALL). A study now identifies small-molecule inhibitors of sarco/endoplasmatic reticulum calcium ATPase (SERCA) channels as Notch1-inhibiting agents (Cancer Cell 23, 390–405).

Kimberley Stegmaier and her colleagues conducted two complementary gene expression–based high-throughput screens of libraries of small-molecule inhibitors and cDNAs in cell lines carrying activated Notch variants. They found that both approaches converged on SERCA activity, such that the most effective compounds inhibited SERCA channel activity and gene expression and the most potent cDNAs encoded SERCA channels.

The authors showed that SERCA inhibition interferes with early maturation of Notch1 in the endoplasmic reticulum, where the receptor is processed by proteases. Cleavage occurs within the heterodimerization domain adjacent to two domains of Notch1 that require Ca2+ for their proper folding. Therefore, the authors suggested that SERCA-mediated Ca2+ influx into the endoplasmic reticulum could support the correct folding and subsequent processing of Notch1. They also showed that mutations in the heterodimerization domain, which are the most frequent type of Notch mutations found in patients with T-ALL, conferred the highest sensitivity to SERCA inhibitors.

The discovery of SERCAs as druggable targets suggests an alternative to γ-secretase inhibitors, which are associated with severe side effects, for the treatment of T-ALL and may also have therapeutic utility in patients with other types of cancer who carry mutant Notch1 variants.