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We identified upregulated, targetable signaling pathways common to both human T-ALL samples and a <jats:italic>Kras<\/jats:italic><jats:sup><jats:italic>LSL-G12D\/+<\/jats:italic><\/jats:sup>.<jats:italic>Mb1<\/jats:italic><jats:sup><jats:italic>Cre\/+<\/jats:italic><\/jats:sup> murine model of T-ALL. We found the NAMPT inhibitor FK866 had the greatest cytotoxicity of a panel of small molecule inhibitors tested in human and mouse T-ALL cell lines, and in patient derived xenograft (PDX)-expanded T-ALL patient samples. We subsequently tested FK866 <jats:italic>in vivo<\/jats:italic> in PDX mouse models of T-ALL, and found that it significantly reduced the peripheral blood disease burden and prolonged the survival of leukemic mice (median survival of 60.5 vs 21 days, p\u2009=\u20090.0007). This screen for targetable pathways in T-ALL generated <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> preclinical data supporting NAMPT inhibition as a promising strategy for the treatment of T-ALL.<\/jats:p>","DOI":"10.1371\/journal.pone.0324443","type":"journal-article","created":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T17:35:25Z","timestamp":1750181725000},"page":"e0324443","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Efficacy of NAMPT inhibition in T-cell acute lymphoblastic 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