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Synergistic antileukemic therapies in NOTCH1-induced T-ALL

Significance The clinical development of targeted therapies has been hampered by their limited intrinsic antitumor activity and the rapid emergence of resistance, highlighting the need to identify highly active and synergistic drug combinations. However, empirical synergistic drug-screening approaches are challenging, and elucidating the mechanisms that underlie such drug interactions is typically complex. Here, we performed an expression-based screen and network analyses to identify drugs amplifying the antitumor effects of NOTCH inhibition in T-cell acute lymphoblastic leukemia (T-ALL). These studies uncovered a druggable synthetic lethal interaction between suppression of protein translation and NOTCH inhibition in T-ALL. Our results illustrate the power of expression-based analyses toward the identification and functional characterization of antitumor drug combinations for the treatment of human cancer. 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.