Dual NAMPT and BTK Targeting Leads to Synergistic Killing of Waldenström Macroglobulinemia Cells Regardless of MYD88 and CXCR4 Somatic Mutation Status

Abstract

Purpose Nicotinamide phosphoribosyltransferase (Nampt) regulates intracellular NAD+ pool and is highly expressed in a number of malignancies. FK866, a selective inhibitor of Nampt, depletes intracellular NAD+ levels, thereby blocking cellular metabolism and triggering sensitization to other drugs and cell death. Here we characterized the anti-tumor effects of Nampt inhibition in Waldenström Macroglobulinemia (WM). Experimental Design We investigated Nampt role in MW cells using both mRNA and protein expression analyses. We have also used loss-of-function approaches to investigate the growth and survival effects of Nampt on MW cells and further tested the anti-MW activity of dual Nampt and BTK inhibition in vitro and in vivo. Results We found that WM cells exhibit high levels of Nampt compared with normal B cells. Loss of function studies suggested a potential oncogenic role of Nampt in WM cells, and BTK-inhibitor ibrutinib and FK866 resulted in a significant and synergistic anti-WM cell death, regardless of MYD88 and CXCR4 mutational status. Cell death was associated with: 1) activation of caspase-3, PARP and down-regulation of Mcl-1; 2) enhanced intracellular ATP and NAD+ depletion; 3) inhibition of NF-kappa B signaling; and 4) inhibition of multiple pro-survival signaling pathways. In a murine xenograft WM model, low-dose combination FK866 and Ibrutinib is well tolerated, significantly inhibits tumor growth, and prolongs host survival. Conclusions our results show intracellular NAD+ level as crucial for proliferation and survival of WM cells, and provides the mechanistic preclinical rationale for targeting Nampt, either alone or with Ibrutinib, to overcome drug resistance and improve patient outcome in WM.

Beyond Energy Metabolism: Exploiting the Additional Roles of NAMPT for Cancer Therapy

“…In addition to the oncogenic signaling molecules already described, correlative studies have also proposed a link between NAMPT expression and EGFR (44, 126), HER2, and estrogen receptor positivity (127). Furthermore, based on the data supporting crosstalk between oncogenic signaling and NAMPT, co-targeting NAMPT along with other signaling pathway molecules, as has been described with the BTK inhibitor ibrutinib in Waldenstrom macroglobulinemia cells, could be a promising therapeutic strategy (128).…”

An HK2 Antisense Oligonucleotide Induces Synthetic Lethality in HK1−HK2+ Multiple Myeloma

“…Most tissues express only HK1; liver expresses only HK4 (also known as glucokinase). However, although HK2 is expressed in only a few normal tissues (e.g., heart, muscle, adipose tissue) and is expendable when globally deleted in adult mice (7), most tumors, regardless of tissue of origin, express HK2 in addition to HK1 (7)(8)(9)(10)(11).…”

Cancer cell metabolic plasticity allows resistance to NAMPT inhibition but invariably induces dependence on LDHA

“…New NAMPT inhibitors are under development which will hopefully overcome these limitations [ 16 ]. In addition, given the unique mode of action of NAMPT inhibitors, their association with other types of anticancer agents, such as chemotherapeutics, ibrutinib, bortezomib, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and cyclosporine-A, has been proposed as a way to boost the efficacy of single treatments [ 17 – 22 ].…”