Efficacy of NAMPT inhibition in T-cell acute lymphoblastic leukemia

PMCID: PMC12173385

PMID: 40526635

DOI: 10.1371/journal.pone.0324443

Journal: PloS one

Publication Date: 2025-6-17

Authors: Vrana C, Zhang M, Rochette M, Alozie M, Oviedo H, et al.

Key Points

• NAMPT inhibition represents a promising targeted therapeutic approach for T-ALL
• FK866 increased median survival by 39.5 days in preclinical mouse models (p=0.0007)
• Potential for selective targeting of leukemic cells while minimizing damage to normal lymphocytes

Summary

This preclinical study investigated novel therapeutic strategies for T-cell acute lymphoblastic leukemia (T-ALL) by identifying and targeting upregulated signaling pathways. Using a comprehensive approach combining RNA sequencing in both human and murine T-ALL models, researchers discovered common dysregulated pathways including E2F, G2M checkpoint, Myc, and mTOR signaling. The study systematically screened small molecule inhibitors and found that the NAMPT inhibitor FK866 demonstrated the most potent cytotoxicity across multiple T-ALL cell lines and patient-derived xenograft (PDX) models.

The most significant finding was FK866's remarkable in vivo efficacy, significantly prolonging survival in leukemic mice (median survival increased from 21 to 60.5 days, p=0.0007). Mechanistically, the drug's effectiveness was linked to reduced NAMPT/Nampt expression in T-ALL samples, which correlated with increased sensitivity to the inhibitor. The research also demonstrated that FK866 induces apoptosis in T-ALL cell lines and could potentially spare normal human lymphocytes, suggesting a promising therapeutic window for future clinical development.