MYC dependency in GLS1 and NAMPT is a therapeutic vulnerability in multiple myeloma

Multiple myeloma (MM) is an incurable hematological malignancy in which MYC alterations contribute to the malignant phenotype. Nevertheless, MYC lacks therapeutic druggability. Here, we leveraged large-scale loss-of-function screens and conducted a small molecule screen to identify genes and pathway...

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Published in:iScience 2024-04, Vol.27 (4), p.109417-109417, Article 109417
Main Authors: Hasan Bou Issa, Lama, Fléchon, Léa, Laine, William, Ouelkdite, Aicha, Gaggero, Silvia, Cozzani, Adeline, Tilmont, Remi, Chauvet, Paul, Gower, Nicolas, Sklavenitis-Pistofidis, Romanos, Brinster, Carine, Thuru, Xavier, Touil, Yasmine, Quesnel, Bruno, Mitra, Suman, Ghobrial, Irene M., Kluza, Jérôme, Manier, Salomon
Format: Article
Language:English
Subjects:
Cancer
Life Sciences
Metabolomics
Transcriptomics
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Summary:Multiple myeloma (MM) is an incurable hematological malignancy in which MYC alterations contribute to the malignant phenotype. Nevertheless, MYC lacks therapeutic druggability. Here, we leveraged large-scale loss-of-function screens and conducted a small molecule screen to identify genes and pathways with enhanced essentiality correlated with MYC expression. We reported a specific gene dependency in glutaminase (GLS1), essential for the viability and proliferation of MYC overexpressing cells. Conversely, the analysis of isogenic models, as well as cell lines dataset (CCLE) and patient datasets, revealed GLS1 as a non-oncogenic dependency in MYC-driven cells. We functionally delineated the differential modulation of glutamine to maintain mitochondrial function and cellular biosynthesis in MYC overexpressing cells. Furthermore, we observed that pharmaceutical inhibition of NAMPT selectively affects MYC upregulated cells. We demonstrate the effectiveness of combining GLS1 and NAMPT inhibitors, suggesting that targeting glutaminolysis and NAD synthesis may be a promising strategy to target MYC-driven MM. [Display omitted] •MYC overexpressing (MYC OE) cells are selectively dependent on glutaminase (GLS1)•GLS1 dependency in MYC-driven cells is non-oncogenic•CB-839 reduces OXPHOS and cellular biosynthesis and has anti-tumor effect in MM•GLS1 inhibition synergizes with NAMPT inhibition to block OXPHOS in MYC OE MM Cancer; Metabolomics; Transcriptomics
ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2024.109417