Targeting oncogenic Notch signaling with SERCA inhibitors

P-type ATPase inhibitors are among the most successful and widely prescribed therapeutics in modern pharmacology. Clinical transition has been safely achieved for H⁺/K⁺ ATPase inhibitors such as omeprazole and Na⁺/K⁺-ATPase inhibitors like digoxin. However, this is more challenging for Ca²⁺-ATPase modulators due to the physiological role of Ca²⁺ in cardiac dynamics. Over the past two decades, sarco-endoplasmic reticulum Ca²⁺-ATPase (SERCA) modulators have been studied as potential chemotherapy agents because of their Ca²⁺-mediated pan-cancer lethal effects. Instead, recent evidence suggests that SERCA inhibition suppresses oncogenic Notch1 signaling emerging as an alternative to γ-secretase modulators that showed limited clinical activity due to severe side effects. In this review, we focus on how SERCA inhibitors alter Notch1 signaling and show that Notch on-target-mediated antileukemia properties of these molecules can be achieved without causing overt Ca²⁺ cellular overload.