NAD+ metabolism restriction boosts high-dose melphalan efficacy in patients with multiple myeloma

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.

Authors

Institutions

Publication Details

Journal
Blood Advances
Published
2024-12-11
DOI
https://doi.org/10.1182/bloodadvances.2024013425
Citations
3
Primary Topic
Sirtuins and Resveratrol in Medicine
Type
article
Field-Weighted Citation Impact
1.03

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

NAD+ metabolism restriction boosts high-dose melphalan efficacy in patients with multiple myeloma

Mario Passalacqua, Alessio Nencioni, Fabio Guolo, Roberto Massimo Lemoli et al.
3 citations
Blood Advances
Sirtuins and Resveratrol in Medicine
1.03
article

NAD+ metabolism restriction boosts high-dose melphalan efficacy in patients with multiple myeloma

Mario Passalacqua, Alessio Nencioni, Fabio Guolo, Roberto Massimo Lemoli, Santina Bruzzone, Michele Cea, Sara Aquino, Aimable Nahimana, Fiammetta Monacelli, Gianluca Santamaria, Adithya Chedere, Pamela Becherini, Matteo Garibotto, Axel Bellotti, Elisa Gelli, Luca Mastracci, Antonia Cagnetta, Claudia Martinuzzi, Emanuele Angelucci, Silvia Ravera, Debora Soncini, Moustafa Ghanem, Francesco Piacente, Nagasuma R Chandra, Giulia Giorgetti, Francesco Ladisa, Michel A. Duchosal, Claudia Veneziano
article en
3 citations

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.

Blood AdvancesVol. 9(5)
Centre Hospitalier Universitaire Vaudois (CH), TUM Klinikum (DE), Italian Institute of Technology (IT), Magna Graecia University (IT), Dana-Farber Cancer Institute (US), Ospedale Policlinico San Martino (IT), Indian Institute of Science Bangalore (IN), University of Genoa (IT), University of Lausanne (CH)
Multiple Myeloma Research Foundation, Ministero della Salute, Università degli Studi di Genova, Associazione Italiana per la Ricerca sul Cancro
Good health and well-being
Openalex Percentile: Top 23%
Sirtuins and Resveratrol in Medicine
1.03
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.