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.