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

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Mantle cell lymphoma (MCL) with TP53 mutations has poor chemotherapy response.
• Novel therapeutic strategies are crucial for high-risk MCL.
• NAMPT, a key enzyme in NAD+ salvage, is overexpressed in MCL.

Purpose of the Study:

• To investigate NAMPT as a therapeutic target in MCL.
• To explore the efficacy of NAMPT inhibition (KPT-9274) in MCL cells.
• To elucidate the differential mechanisms of NAMPT inhibition based on TP53 status.

Main Methods:

• Assessed KPT-9274 effects on MCL cell viability and apoptosis.
• Investigated DNA damage response (DDR) and B-cell receptor (BCR) signaling pathways.
• Evaluated synergistic effects with standard therapies and in vivo efficacy in xenograft models.

Main Results:

• KPT-9274 reduced MCL cell viability and induced apoptosis regardless of TP53 status.
• TP53-mutant MCL cells showed synthetic lethality via DDR disruption.
• TP53 wild-type MCL cells exhibited suppressed BCR signaling and immune checkpoints.
• NAMPT inhibition sensitized TP53-mutant MCL to alkylating/DDR agents and TP53 wild-type MCL to overcome BTK inhibitor resistance.
• Combination therapy achieved significant tumor regression in vivo with acceptable toxicity.

Conclusions:

• NAMPT is a viable therapeutic target in MCL, with distinct mechanisms based on TP53 mutation status.
• TP53 status-guided NAMPT inhibitor combinations offer a precision medicine approach for MCL.
• Clinical evaluation of these combinations is warranted to address chemoresistance in high-risk MCL.