Inhibition of NAMPT targets DNA damage response to sensitize alkylating chemotherapy in TP53 mutant mantle cell lymphoma
- Blood Adv. 2025 Dec 22:bloodadvances.2025016765. doi: 10.1182/bloodadvances.2025016765.
- 1. School of Life Sciences, Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University, Dalian, 116082, PR China; Department of Medical Oncology, the Second Hospital of Dalian Medical University, Dalian, 116023, China.
- 2. Department of Medical Oncology, the Second Hospital of Dalian Medical University, Dalian, 116023, Dalian, China.
- 3. State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, Dalian, China.
- 4. LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana- Farber Cancer Institute, Harvard Medical School, Boston, MA; State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China; Tianjin Institutes of Health Science, Tianjin 301600, China.
- 5. Department of Pathology, the Second Hospital of Dalian Medical University, Dalian, 116023, Dalian, China.
- 6. School of Life Sciences, Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University, Dalian, 116082, Dalian, China.
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.