Repurposing NAMPT inhibitors for germinal center B-cell-like diffuse large B-cell lymphoma.

Diffuse Large B-cell lymphoma (DLBCL) includes the Activated B-cell-like (ABC) and Germinal Center B-cell-like (GCB) subtypes, which differ in cell-of-origin, genetics and clinical response. By screening the subtype-specific activity of 211 drugs approved or in active clinical development for other diseases, we identified inhibitors of nicotinamide phosphoribosyl transferase (NAMPTi) as active in a subset of GCB-DLBCLs in vitro and in vivo. We validated three chemically distinct NAMPTi for their on-target activity based on biochemical and genetic rescue approaches, and found the ratio between NAMPT:PARP1 RNA levels was predictive of NAMPTi sensitivity across DLBCL subtypes. Notably, the NAMPT:PARP1 transcript ratio predicts higher anti-tumor activity in BCL2-translocated GCB-DLBCL. Accordingly, pharmacological and genetic inhibition of BCL2 was potently synergistic with NAMPT blockade. These data support the inhibition of NAMPT as a therapeutically relevant strategy for BCL2-translocated DLBCLs.