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

Patients with TP53 mutant mantle cell lymphoma (MCL) face poor chemotherapy response and early progression, requiring novel therapies. Nicotinamide phosphoribosyl transferase (NAMPT), the rate-limiting nicotinamide adenine dinucleotide 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, whereas in TP53 wild-type cells, it selectively suppresses B-cell receptor (BCR) 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.