NAD+ metabolism restriction boosts high-dose melphalan efficacy in patients with multiple myeloma
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| Title: | NAD+ metabolism restriction boosts high-dose melphalan efficacy in patients with multiple myeloma |
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| Authors: | Soncini, Debora, Becherini, Pamela, Ladisa, Francesco, Ravera, Silvia, Chedere, Adithya, Gelli, Elisa, Giorgetti, Giulia, Martinuzzi, Claudia, Piacente, Francesco, Mastracci, Luca, Veneziano, Claudia, Santamaria, Gianluca, Monacelli, Fiammetta, Ghanem, Moustafa S, Cagnetta, Antonia, Guolo, Fabio, Garibotto, Matteo, Aquino, Sara, Passalacqua, Mario, Bruzzone, Santina, Bellotti, Axel, Duchosal, Michel A, Nahimana, Aimable A, Angelucci, Emanuele, Nagasuma, Chandra, Nencioni, Alessio, Lemoli, Roberto Massimo, Cea, Michele |
| Source: | Blood Adv Blood Advances, Vol 9, Iss 5, Pp 1024-1039 (2025) Blood advances, vol. 9, no. 5, pp. 1024-1039 |
| Publisher Information: | American Society of Hematology, 2025. |
| Publication Year: | 2025 |
| Subject Terms: | 0301 basic medicine, 0303 health sciences, 03 medical and health sciences, RC581-951, Multiple Myeloma/drug therapy, Multiple Myeloma/metabolism, Multiple Myeloma/pathology, Humans, NAD/metabolism, Nicotinamide Phosphoribosyltransferase/metabolism, Nicotinamide Phosphoribosyltransferase/genetics, Nicotinamide Phosphoribosyltransferase/antagonists & inhibitors, Melphalan/pharmacology, Melphalan/therapeutic use, Melphalan/administration & dosage, Cell Line, Tumor, Pentosyltransferases/metabolism, Pentosyltransferases/genetics, Cytokines/metabolism, Specialties of internal medicine, Plasma Cell Disorders |
| Description: | Abstract Elevated levels of the NAD+-generating enzyme nicotinamide phosphoribosyltransferase (NAMPT) are a common feature across numerous cancer types. Accordingly, we previously reported pervasive NAD+ dysregulation in multiple myeloma (MM) cells in association with upregulated NAMPT expression. Unfortunately, albeit being effective in preclinical models of cancer, NAMPT inhibition has proven ineffective in clinical trials because of the existence of alternative NAD+ production routes using NAD+ precursors other than nicotinamide. Here, by leveraging mathematical modeling approaches integrated with transcriptome data, we defined the specific NAD+ landscape of MM cells and established that the Preiss-Handler pathway for NAD+ biosynthesis, which uses nicotinic acid as a precursor, supports NAD+ synthesis in MM cells via its key enzyme nicotinate phosphoribosyltransferase (NAPRT). Accordingly, we found that NAPRT confers resistance to NAD+-depleting agents. Transcriptomic, metabolic, and bioenergetic profiling of NAPRT-knockout (KO) MM cells showed these to have weakened endogenous antioxidant defenses, increased propensity to oxidative stress, and enhanced genomic instability. Concomitant NAMPT inhibition further compounded the effects of NAPRT-KO, effectively sensitizing MM cells to the chemotherapeutic drug, melphalan; NAPRT added-back fully rescues these phenotypes. Overall, our results propose comprehensive NAD+ biosynthesis inhibition, through simultaneously targeting NAMPT and NAPRT, as a promising strategy to be tested in randomized clinical trials involving transplant-eligible patients with MM, especially those with more aggressive disease. |
| Document Type: | Article Other literature type |
| File Description: | application/pdf |
| Language: | English |
| ISSN: | 2473-9537 2473-9529 |
| DOI: | 10.1182/bloodadvances.2024013425 |
| Access URL: | https://pubmed.ncbi.nlm.nih.gov/39661983 https://doaj.org/article/597a206371e14f2eafa28f986e80aa00 https://serval.unil.ch/notice/serval:BIB_6A1D49B7E1D9 http://nbn-resolving.org/urn/resolver.pl?urn=urn:nbn:ch:serval-BIB_6A1D49B7E1D95 https://serval.unil.ch/resource/serval:BIB_6A1D49B7E1D9.P001/REF.pdf https://hdl.handle.net/11567/1226642 https://doi.org/10.1182/bloodadvances.2024013425 |
| Rights: | CC BY NC ND |
| Accession Number: | edsair.doi.dedup.....0419460c59883f06e8545ce9de4c7f8b |
| Database: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstract: | Abstract Elevated levels of the NAD+-generating enzyme nicotinamide phosphoribosyltransferase (NAMPT) are a common feature across numerous cancer types. Accordingly, we previously reported pervasive NAD+ dysregulation in multiple myeloma (MM) cells in association with upregulated NAMPT expression. Unfortunately, albeit being effective in preclinical models of cancer, NAMPT inhibition has proven ineffective in clinical trials because of the existence of alternative NAD+ production routes using NAD+ precursors other than nicotinamide. Here, by leveraging mathematical modeling approaches integrated with transcriptome data, we defined the specific NAD+ landscape of MM cells and established that the Preiss-Handler pathway for NAD+ biosynthesis, which uses nicotinic acid as a precursor, supports NAD+ synthesis in MM cells via its key enzyme nicotinate phosphoribosyltransferase (NAPRT). Accordingly, we found that NAPRT confers resistance to NAD+-depleting agents. Transcriptomic, metabolic, and bioenergetic profiling of NAPRT-knockout (KO) MM cells showed these to have weakened endogenous antioxidant defenses, increased propensity to oxidative stress, and enhanced genomic instability. Concomitant NAMPT inhibition further compounded the effects of NAPRT-KO, effectively sensitizing MM cells to the chemotherapeutic drug, melphalan; NAPRT added-back fully rescues these phenotypes. Overall, our results propose comprehensive NAD+ biosynthesis inhibition, through simultaneously targeting NAMPT and NAPRT, as a promising strategy to be tested in randomized clinical trials involving transplant-eligible patients with MM, especially those with more aggressive disease. |
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| ISSN: | 24739537 24739529 |
| DOI: | 10.1182/bloodadvances.2024013425 |