2. Academic Validation
  3. Inhibition of NAMPT targets DNA damage response to sensitize alkylating chemotherapy in TP53 mutant mantle cell lymphoma

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.
Na Li 1,  Yicen Liu 2,  Linna Zhang 2,  Saisai Guo 2,  Zhihao Wu 3,  Yan Xu 4,  Ming Yang 2,  Jixia Kong 5,  Yuxuan Che 2,  Kun Shao 3,  Hong Yang 6
Affiliations

Affiliations

  • 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.
PMID: 41428986 DOI: 10.1182/bloodadvances.2025016765
Abstract

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.

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