Redler Jansen, Nelson Ariana E, Heske Christine M
Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Cancer Drug Resist. 2025 Apr 16;8:18. doi: 10.20517/cdr.2024.216. eCollection 2025.
A common barrier to the development of effective anticancer agents is the development of drug resistance. This obstacle remains a challenge to successful clinical translation, particularly for targeted agents. Nicotinamide phosphoribosyltransferase (NAMPT) inhibitors represent a clinically applicable drug class that exploits the increased dependence of cancer cells on nicotinamide adenine dinucleotide (NAD), a coenzyme essential to metabolism and other cellular functions. NAMPT catalyzes the rate-limiting step in the NAD salvage pathway of mammalian cells and is overexpressed in numerous types of cancers. Preclinical research has demonstrated that pharmacological targeting of NAMPT may be an effective strategy against certain cancers, and while several early-phase clinical trials testing NAMPT inhibitors in refractory cancers have been completed, drug resistance is a concern. Preclinical work in a variety of cancer models has demonstrated the emergence of resistance to multiple NAMPT inhibitors through several recurrent mechanisms. This review represents the first article summarizing the current state of knowledge regarding the mechanisms of acquired drug resistance to NAMPT inhibitors with a particular focus on upregulation of the compensatory NAD production enzymes nicotinate phosphoribosyltransferase (NAPRT) and quinolinate phosphoribosyltransferase (QPRT), acquired mutations in NAMPT, metabolic reprogramming, and altered expression of the ATP-binding cassette (ABC) efflux transporter ABCB1. An understanding of how these mechanisms interact with the biology of each given cancer cell type to predispose to the acquisition of NAMPT inhibitor resistance will be necessary to develop strategies to optimize the use of these agents moving forward.
有效抗癌药物研发的一个常见障碍是耐药性的产生。这一障碍仍然是成功进行临床转化的挑战，尤其是对于靶向药物而言。烟酰胺磷酸核糖转移酶（NAMPT）抑制剂代表了一类临床适用的药物，这类药物利用癌细胞对烟酰胺腺嘌呤二核苷酸（NAD）依赖性的增加，NAD是代谢和其他细胞功能所必需的辅酶。NAMPT催化哺乳动物细胞NAD补救途径中的限速步骤，并且在多种癌症类型中过表达。临床前研究表明，对NAMPT进行药物靶向可能是对抗某些癌症的有效策略，虽然已经完成了几项在难治性癌症中测试NAMPT抑制剂的早期临床试验，但耐药性仍是一个问题。在多种癌症模型中的临床前研究表明，通过几种反复出现的机制会出现对多种NAMPT抑制剂的耐药性。这篇综述是第一篇总结关于对NAMPT抑制剂获得性耐药机制的当前知识状态的文章，特别关注补偿性NAD产生酶烟酸磷酸核糖转移酶（NAPRT）和喹啉酸磷酸核糖转移酶（QPRT）的上调、NAMPT中的获得性突变、代谢重编程以及ATP结合盒（ABC）外排转运蛋白ABCB1的表达改变。了解这些机制如何与每种特定癌细胞类型的生物学相互作用以导致获得NAMPT抑制剂耐药性，对于制定优化这些药物未来使用的策略是必要的。
