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Metabolic Heterogeneity in Diffuse Large B-Cell Lymphoma Cells Reveals an Innovative Antimetabolic Combination Strategy
by
, , , , , , , ,
Leonardo Lordello
1,†, 
Stéphanie Nuan-Aliman
1,†,
Karoline Kielbassa-Elkadi
1,†,
Aurélie Montagne
1,
Konstantina Kotta
1,
Isabelle Martins
2,3,
Eva Pinto Jurado
1,
Cédric Caradeuc
4,
Jacqueline Lehmann-Che
5,6,
José Ángel Martínez-Climent
7,
Véronique Meignin
1,8,
Nicolas Giraud
4,
Guido Kroemer
2,3,9
,
Gildas Bertho
4
,
Catherine Thieblemont
1,10 and
Véronique Baud
1,*
1
NF-κB, Differentiation and Cancer, Université Paris Cité, 75006 Paris, France
2
INSERM U1138, Equipe Labellisée Ligue Contre le Cancer, Cordeliers Research Center, Université Paris Cité, Sorbonne Université, 75006 Paris, France
3
Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, 94805 Villejuif, France
4
Laboratory of Pharmacological and Toxicological Chemistry and Biochemistry, LPTCB, Université Paris Cité, Sorbonne Paris Cité, UMR CNRS 8601, 75006 Paris, France
5
INSERM U976, Immunologie Humaine, Pathophysiologie, Immunothérapie, Université Paris Cité, 75010 Paris, France
6
Service d’Oncologie moléculaire, AP-HP, Hôpital Saint-Louis, 75010 Paris, France
7
Department of Hematology, Center for Applied Medical Research, University of Navarra, IDISNA, CIBERONC, 31008 Pamplona, Spain
8
Department of Pathology, AP-HP, Hôpital Saint-Louis, 75010 Paris, France
9
Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France
10
Assistance Publique—Hôpitaux de Paris, Hôpital Saint Louis, Hémato-Oncologie, 1 Avenue Claude Vellefaux, 75010 Paris, France
*
Author to whom correspondence should be addressed.
†
These authors have contributed equally to this work.
Cancers 2025, 17(3), 394; https://doi.org/10.3390/cancers17030394
Submission received: 21 November 2024
/
Revised: 12 December 2024
/
Accepted: 21 January 2025
/
Published: 24 January 2025
(This article belongs to the Section Cancer Therapy)
Simple Summary
Diffuse large B-cell lymphoma (DLBCL) is a very common and aggressive form of blood cancer. Despite therapeutic advances, ~40% of DLBCL patients will die. Metabolic reprogramming is a characteristic of cancer cells and a new potential therapeutic target. Our research focuses on developing strategies by targeting metabolic vulnerabilities to improve clinical outcomes for DLBCL patients with therapeutic impasses. Here, we report that combining two antimetabolic drugs, namely metformin and L-asparaginase, induced massive DLBCL cell killing compared to each drug alone. Further, we deciphered how this novel drug combination impacts critical metabolic and oncogenic pathways. Finally, we demonstrated the clinical benefit of this optimized antimetabolic drug treatment for DLBCL patients. Altogether, our data provide a framework for the use of an optimized combination of antimetabolic drugs to overcome resistance in DLBCL patients.
Abstract
Background/Objectives: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, characterized by aggressive and heterogeneous tumors originating from B-cells. Especially in patients with relapsed or refractory (R/R) disease, DLBCL remains a challenging cancer to treat. Metabolic reprogramming is a hallmark of malignant cells. Our research focuses on developing strategies to enhance clinical outcomes for R/R DLBCL patients by targeting metabolic vulnerabilities. Methods: We investigated the effects of combining metformin and L-asparaginase, two FDA-approved antimetabolic drugs, on DLBCL cell metabolism and survival. Nuclear magnetic resonance (NMR) spectroscopy was employed to assess metabolic disturbances induced by the drug combination. The impact on lipid metabolism, glycolysis, glutaminolysis, the tricarboxylic acid (TCA) cycle, and antioxidant responses was examined. Induction of apoptosis was evaluated by FACS analysis. Results: The combination of metformin and L-asparaginase strongly sensitized DLBCL cells to apoptosis, independently of their oxidative phosphorylation (OxPhos) or BCR/glycolytic status. NMR spectroscopy revealed that this combination induces broader metabolic disturbances than either drug alone. It disrupts lipid metabolism by altering levels of phospholipids, cholesterol, and fatty acids. Additionally, it counteracts the pro-glycolytic effect of metformin, decreases glycolysis, and reduces glutaminolysis. It also affects the TCA cycle and antioxidant responses, critical for cellular energy production and redox balance. Furthermore, this combination interferes with two key cancer survival pathways, mTORC1 and MAPK signaling. Importantly, proof of principle for its beneficial effect was demonstrated in DLBCL patients. Conclusions: Combining metformin and L-asparaginase affects DLBCL cell survival by targeting multiple metabolic pathways and may represent a novel therapeutic approach for R/R DLBCL patients.
