Cancer research has made remarkable progress in the last decades and the development of new therapeutics contributed to the improvement of cancer treatment. However, many cancers remain uncurable today. In order to develop effective therapeutic strategies, it is crucial to identify specific vulnerabilities of cancer cells, their mechanisms of adaptation to therapy-induced stresses, and the mechanisms of therapy-resistance acquisition.
Nicotinamide phosphoribosyltransferase (NAMPT) inhibitors have been developed and extensively studied as promising anticancer agents. NAMPT inhibitors display selective cytotoxicity toward cancer cells by depleting cellular nicotinamide adenine dinucleotide (NAD), an essential molecule in cell functions and survival. However, the efficacy of NAMPT inhibitors is limited in clinical settings. Further investigations are needed to determine the molecular mechanisms involved in the antitumor effect of NAMPT inhibitors, as well as factors that modulate tumor response to NAMPT inhibitors.
In this study, we aimed to characterize the mechanisms by which leukemia and lymphoma cells gain resistance to NAMPT inhibitor APO866 through three distinct projects.
First, to investigate the molecular mechanisms contributing to the development of resistance to APO866, we generated acute myeloid leukemia (AML) models of in vivo-acquired resistance, using human AML cell line ML2 xenografts in mice. We performed whole transcriptomic analyses of resistant ML2 by RNA sequencing, combined with functional studies, to identify the alterations associated with resistance to APO866. We demonstrated that acquired resistance is conferred by a profound transcriptomic reprogramming that induces the activation of cellular pro-survival signaling as well as adaptive metabolic changes.
In the second project, to examine the possible involvement of gut microbiota in human NAD metabolome and in tumor response to NAMPT inhibitors, we performed studies using bacteria -infected cell cultures, as well as ML2 xenograft models in microbiota-depleted mice. Overall, we showed that gut microbiota-dependent conversion of NAD-related metabolites contributes to NAD homeostasis in distant tumor cells. This counteracts the effect of NAMPT inhibitors and therefore decreases their efficacy as antitumoral agent.
Finally, we identified a novel precursor of NAD biosynthesis that can be exploited by leukemia cells treated with NAMPT inhibitors to suppress its anticancer toxicity.
In summary, this work provides novel evidence that the efficacy of NAMPT inhibitors in hematological cancers can be affected by gut microbiota or by the presence of a previously
unidentified NAD biosynthesis precursor. Furthermore, we characterized models of acquired resistance to APO866, generated in vivo. This is also the first study to report transcriptomic analyses that investigate the gene expressions associated with the NAMPT inhibitor treatment and with resistance to NAMPT inhibitors. Overall, the use of combinatory approaches with NAMPT inhibitors appear to be promising to overcome their limited efficacy in the clinics and the resistance acquisition. These findings will contribute to the development of therapeutic strategies to treat cancers with NAMPT inhibitors.