Metabolic heterogeneity in DLBCL cells reveals an innovative antimetabolic combination strategy

<title>Abstract</title> 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 the clinical outcomes for R/R DLBCL patients by targeting metabolic vulnerabilities. Here we report that the combination of metformin and L-asparaginase, two FDA-approved antimetabolic drugs, strongly sensitizes DLBCL cells to apoptosis, independently of their OxPhos or BCR/glycolytic status. The combination of metformin with L-asparaginase strongly impacts various metabolic liabilities, including glutaminolysis, lipid metabolism, TCA cycle and redox responses. In addition, this combination of antimetabolic drugs interferes with two critical pathways involved in cancer survival, namely the mTOR and MAPK oncogenic pathways. Most importantly, we obtained the proof of principle of the beneficial effect of the metformin and L-asparaginase combination in DLBCL patients. Taken together, our findings establish that combining metformin and L-asparaginase affects DLBCL cell survival by targeting multiple metabolic pathways and hence may represent a new approach for the treatment of R/R DLBCL patients. <bold>*Leonardo Lordello, Stéphanie Nuan-Aliman, and Karoline Kielbassa-Elkadi are co-first authors.</bold>