Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL). B-cell NHLs rely on Bruton's tyrosine kinase (BTK) mediated B-cell receptor signaling for survival and disease progression. However, they are often resistant to BTK inhibitors or soon acquire resistance after drug exposure. Upon reaching drug tolerance, B-cell NHL cells proliferate faster, which suggests increased metabolic activity. In this study, we explored the onco-metabolic regulators of ibrutinib -resistant activated B-cell (ABC) DLBCL using a ‘multi-omics' analysis that integrated metabolomics (using high-resolution mass spectrometry) and transcriptomics (gene expression analysis). We performed unbiased statistical analyses to uncover dysregulated metabolic pathways among the proteomic and transcriptomic datasets. Overlay of the analyses identified two significantly altered metabolic pathways at both the metabolic and transcript level. Gene-metabolite integration revealed interleukin 4 induced 1 (IL4I1) at the crosstalk of two significantly altered metabolic pathways involved in the production of various amino acids. We showed for the first time that a metabolic shift from glycolysis towards oxidative phosphorylation in these lymphomas is activated via the BTK-PI3K-AKT-IL4I1 axis and can be targeted therapeutically. These findings from our unbiased analyses highlight the role of metabolic dysregulation during drug resistance development. Furthermore, our work demonstrates that a multi-omics approach can be a powerful and unbiased strategy to uncover genes and pathways that drive metabolic dysregulation in cancer cells.

Citation Format: Satishkumar Singh, Fouad Choueiry, Amber Hart, Anuvrat Sircar, Jiangjiang Zhu, Lalit Sehgal. Multiomics integration elucidates onco-metabolic modulators of drug resistance in lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2351.