Synergistic antileukemic therapies in NOTCH1-induced T-ALL
Menée in vitro, in vivo et à l'aide de l'algorithme DeMAND (Detecting Mechanism of Action based Network Dysregulation), cette étude identifie, pour les leucémies lymphoblastiques aiguës à lymphocytes T, des traitements ayant un effet synergique avec des inhibiteurs de NOTCH1
The Notch1 gene is a major oncogenic driver and therapeutic target in T-cell acute lymphoblastic leukemia (T-ALL). However, inhibition of NOTCH signaling with
γ-secretase inhibitors (GSIs) has shown limited antileukemic activity in clinical trials. Here we performed an expression-based virtual screening to identify highly active antileukemic drugs that synergize with NOTCH1 inhibition in T-ALL. Among these, withaferin A demonstrated the strongest cytotoxic and GSI-synergistic antileukemic effects in vitro and in vivo. Mechanistically, network perturbation analyses showed eIF2A-phosphorylation
–mediated inhibition of protein translation as a critical mediator of the antileukemic effects of withaferin A and its interaction with NOTCH1 inhibition. Overall, these results support a role for anti-NOTCH1 therapies and protein translation inhibitor combinations in the treatment of T-ALL.