Inhibition of NAMPT targets DNA damage response to sensitize alkylating chemotherapy in TP53 mutant mantle cell lymphoma Open Access

• NAMPT is a TP53-stratified therapeutic target in MCL.

• NAMPT inhibitors synergize with DDR agents to overcome TP53-mutant chemoresistance without added toxicity.

TP53-mutant mantle cell lymphoma (MCL) patients face poor chemotherapy response and early progression, requiring novel therapies. We identify NAMPT, the rate-limiting NAD+ salvage enzyme, overexpressed in MCL cell lines and patient tissues, emerges as a therapeutic target. The NAMPT inhibitor KPT-9274 reduced viability and induced apoptosis in MCL cells irrespective of TP53 status. Mechanistic studies reveal a striking dichotomy: in TP53-mutant cells, NAMPT inhibition triggers synthetic lethality through catastrophic DNA damage response (DDR) pathway disruption, while in TP53 wild-type cells, it selectively suppresses B-cell receptor signaling and immune checkpoint activation. This biological divergence translates to clinically actionable synergies-TP53-mutant cells exhibit marked sensitization to alkylating agents and DDR-targeting therapies, whereas TP53 wild-type models show potential for overcoming BTK inhibitor resistance. In vivo studies confirm that NAMPT-based combinations achieve profound tumor regression in TP53-mutant xenografts without exacerbating toxicity. Our findings establish NAMPT as a dual-context therapeutic node, providing a precision medicine framework to circumvent chemoresistance in high-risk MCL. These results advocate for the clinical evaluation of TP53 status-guided NAMPT inhibitor combinations to address this unmet oncologic challenge.