CD38 Deregulation As Strategy to Make Multiple Myeloma Cells More Sensitive to NAD+ Depleting Agents

Background: The upregulated NAD+ biosynthesis, which is needed to face increased proliferation and metabolic processes, represents an important feature distinguishing cancer cells from their normal counterparts. As a result, the NAD+ biosynthetic apparatus emerges as highly promising therapeutic target for tumors, as suggested by the use of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors in a number of malignancies, including Multiple Myeloma (MM) and leukemia (Cea et al. Blood 2012; Cagnetta et al. Blood 2013; Cagnetta et al. CCR 2015). The ecto-enzyme CD38 is emerging as a novel therapeutic target for patients with hematological malignancies, including MM, with several monoclonal antibodies already tested in clinical trials with promising results. Importantly, CD38 by regulating intracellular NAD+ stores acts as member of the intricate network supporting metabolic reprogramming associated with cancer. Based on these assumptions, here we explored CD38 activity as innovative strategy to enhance the anti-tumor activity of NAMPT inhibition in Multiple Myeloma cells.

Methods: A panel of different MM cell lines and primary cells, both sensitive and resistant to conventional and novel anti-MM therapies, was used in the study. The effects of Nampt inhibition was evaluated in presence of CD38-gene editing (loss/gain of approaches) by using CTG assay and Annexin-V/propidium iodide staining. Next, the anti-MM effects of chemicals affecting CD38 activity were also evaluated in combination with low doses of Nampt inhibitors. Mechanistic studies were performed with Western-blotting, lentivirus-mediated shRNAs and enzymatic assays.

Results and Conclusions: By using different approaches, we found that CD38 deregulation makes MM cells more vulnerable to NAD+ depleting agents. Ongoing mechanistic studies suggest the central role played by energetic metabolism in the observed synergism. Overall our data provide the mechanistic preclinical rationale to enhance anti-MM activity of Nampt targeting agents, in order to both overcome drug resistance and improve patients outcome.