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Two compound libraries were screened for repurposing potential, highlighting inhibitors of NAMPT and HDAC with the strongest activity. Hits were validated across expanded neuroendocrine cell lines, and mechanisms were evaluated through metabolic assays, gene expression comparisons, and combination studies. Results showed NAMPT inhibition reduces basal oxidative phosphorylation and energy production, with YAP1 influencing sensitivity, while combined HDAC and NAMPT inhibition produced synergistic activity.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/novel-therapeutic-strategies-exploiting-the-unique-properties-of-neuroendocrine-neoplasms/378354/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/novel-therapeutic-strategies-exploiting-the-unique-properties-of-neuroendocrine-neoplasms/378354.png","ImageObject",300,407,{"name":92,"@type":93},"McGucket","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-27","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":44},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Which drug targets were identified as most active against neuroendocrine tumor-derived cell lines?","Question",{"text":112,"@type":113},"In screenings of two repurposing-oriented compound libraries, NAMPT inhibitors and HDAC inhibitors showed the highest activity against neuroendocrine tumor-derived cell lines.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does NAMPT inhibition drive cell death in sensitive neuroendocrine cell lines?",{"text":117,"@type":113},"NAMPT inhibition reduced basal oxidative phosphorylation and energy production, lowering ATP and NAD+ levels and diminishing citric acid cycle catalytic activity.",{"name":119,"@type":110,"acceptedAnswer":120},"What role does YAP1 play in sensitivity to NAMPT inhibitors?",{"text":121,"@type":113},"Analysis indicated that YAP1 is pivotal in determining sensitivity to NAMPT inhibitors, and mechanistic insight into YAP1 guided combination evaluations.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},378354,1790471762,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":44,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":36},1236954412713,"https://us-avatar.wpscdn.com/davatar_29158cc5080c5b710cf443261637dec0","cancers   \nArticle  \nNovel Therapeutic Strategies Exploiting the Unique Properties of Neuroendocrine Neoplasms  \nMaryam Safari 1, Luigi Scotto 1, Thomas Litman 2, Lubov A. Petrukhin 1, Hu Zhu 3, Min Shen 3, Robert W. Robey 4, Matthew D. Hall 3, Tito Fojo 1,5,6 and Susan E. Bates 1,5,6, *  \nCitation: Safari, M.; Scotto, L.;  \nLitman, T.; Petrukhin, L.A.; Zhu, H.; Shen, M.; Robey, R.W.; Hall, M.D.; Fojo, T.; Bates, S.E. Novel Therapeutic Strategies Exploiting the Unique Properties of Neuroendocrine Neoplasms. Cancers 2023, 15, 4960 . [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)cancers15204960  \nAcademic Editors: Gabriella D'Oraziand Mara Cirone  \nReceived: 21 August 2023  \nRevised: 2 October 2023  \nAccepted: 6 October 2023  \nPublished: 12 October 2023  \nCopyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Division of Hematology/Oncology, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA  \n2 Department of Immunology and Microbiology, University of Copenhagen, 1172 Copenhagen, Denmark  \n3 National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, Rockville, MD 20892, USA  \n4 Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA  \n5 James J. Peters Bronx Veterans Affairs Medical Center, Bronx, NY 10468, USA  \n6 Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA  \n* Correspondence: [seb2227@cumc.columbia.edu](seb2227@cumc.columbia.edu)  \nSimple 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.  \nAbstract: 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 oxidat","cbCaimEqejs4xelG","https://ap.wps.com/l/cbCaimEqejs4xelG","pdf",3370286,16,"English","# Simple Summary\n# Abstract\n# Keywords\n# Introduction","[{\"question\":\"Which drug targets were identified as most active against neuroendocrine tumor-derived cell lines?\",\"answer\":\"In screenings of two repurposing-oriented compound libraries, NAMPT inhibitors and HDAC inhibitors showed the highest activity against neuroendocrine tumor-derived cell lines.\"},{\"question\":\"How does NAMPT inhibition drive cell death in sensitive neuroendocrine cell lines?\",\"answer\":\"NAMPT inhibition reduced basal oxidative phosphorylation and energy production, lowering ATP and NAD+ levels and diminishing citric acid cycle catalytic activity.\"},{\"question\":\"What role does YAP1 play in sensitivity to NAMPT inhibitors?\",\"answer\":\"Analysis indicated that YAP1 is pivotal in determining sensitivity to NAMPT inhibitors, and mechanistic insight into YAP1 guided combination evaluations.\"}]","Novel Therapeutic Strategies - Exploiting the Unique Properties of Neuroendocrine Neoplasms | PDF",1790229634]