Novel Therapeutic Strategies Exploiting the Unique Properties of Neuroendocrine Neoplasms

SIMPLE SUMMARY: The screening of experimental and repurposing drugs has enormous potential for rapid clinical impact, particularly when new therapeutic strategies are sought. By screening two drug libraries, nicotinamide phosphoribosyltransferase (NAMPT) and histone deacetylase (HDAC) inhibitors were identified as agents with the highest activity against neuroendocrine tumor-derived cell lines. An evaluation of different NAMPT inhibitors revealed a reduction in basal oxidative phosphorylation and energy production to be partially but not completely responsible for cell death following the exposure to the drug, with the yes-associated protein 1 (YAP1) playing a pivotal role in the sensitivity to the NAMPT inhibitors. Insight into the contribution of YAP1 guided the evaluation of combinations of HDAC and NAMPT inhibitors for the treatment of neuroendocrine neoplasms. ABSTRACT: Background: Over the last few decades of treatment, the outcomes for at least some subsets of neuroendocrine neoplasms (NENs) have improved. However, the identification of new vulnerabilities for this heterogeneous group of cancers remains a priority. Methods: Using two libraries of compounds selected for potential repurposing, we identified the inhibitors of nicotinamide phosphoribosyltransferase (NAMPT) and histone deacetylases (HDAC) as the agents with the highest activity. We validated the hits in an expanded set of neuroendocrine cell lines and examined the mechanisms of action. Results: In Kelly, NH-6, and NCI-H82, which are two neuroblastoma and one small cell lung cancer cell lines, respectively, metabolic studies suggested that cell death following NAMPT inhibition is the result of a reduction in basal oxidative phosphorylation and energy production. NAMPT is the rate-limiting enzyme in the production of NAD+, and in the three cell lines, NAMPT inhibition led to a marked reduction in the ATP and NAD+ levels and the catalytic activity of the citric acid cycle. Moreover, comparative analysis of the mRNA expression in drug-sensitive and -insensitive cell lines found less dependency of the latter on oxidative phosphorylation for their energy requirement. Further, the analysis of HDAC and NAMPT inhibitors administered in combination found marked activity using low sub-lethal concentrations of both agents, suggesting a synergistic effect. Conclusion: These data suggest NAMPT inhibitors alone or in combination with HDAC inhibitors could be particularly effective in the treatment of neuroendocrine neoplasms.