Lactate Dehydrogenase B and Pyruvate Oxidation Pathway Associated With Carfilzomib-Related Cardiotoxicity in Multiple Myeloma Patients: Result of a Multi-Omics Integrative Analysis

Abstract

Multiple myeloma (MM) is the second most frequent hematologic cancer in the United States. Carfilzomib (CFZ), an irreversible proteasome inhibitor being used to treat relapsed and refractory MM, has been associated with cardiotoxicity, including heart failure. We hypothesized that a multi-omics approach integrating data from different omics would provide insights into the mechanisms of CFZ-related cardiovascular adverse events (CVAEs). Plasma samples were collected from 13 MM patients treated with CFZ (including 7 with CVAEs and 6 with no CVAEs) at the University of Florida Health Cancer Center. These samples were evaluated in global metabolomic profiling, global proteomic profiling, and microRNA (miRNA) profiling. Integrative pathway analysis was performed to identify genes and pathways differentially expressed between patients with and without CVAEs. The proteomics analysis identified the up-regulation of lactate dehydrogenase B (LDHB) [fold change (FC) = 8.2, p = 0.01] in patients who experienced CVAEs. The metabolomics analysis identified lower plasma abundance of pyruvate (FC = 0.16, p = 0.0004) and higher abundance of lactate (FC = 2.4, p = 0.0001) in patients with CVAEs. Differential expression analysis of miRNAs profiling identified mir-146b to be up-regulatein (FC = 14, p = 0.046) in patients with CVAE. Pathway analysis suggested that the pyruvate fermentation to lactate pathway is associated with CFZ-CVAEs. In this pilot multi-omics integrative analysis, we observed the down-regulation of pyruvate and up-regulation of LDHB among patients who experienced CVAEs, suggesting the importance of the pyruvate oxidation pathway associated with mitochondrial dysfunction. Validation and further investigation in a larger independent cohort are warranted to better understand the mechanisms of CFZ-CVAEs.

Development and characterization of three cell culture systems to investigate the relationship between primary bone marrow adipocytes and myeloma cells

“…In donor 1, three proteins were significantly upregulated in the co-culture condition compared with either cell type alone including LDHB, YWHAZ, and EEF1A2. LDHB is upregulated in cancer associated adipocytes in the breast cancer microenvironment, suggesting that cancer cells, including myeloma cells, could modulate lactate metabolism in the microenvironment ( 56 )—a process that might be critical in patient responses to carfilzomib ( 57 ). In the 3D co-culture using cells from donor 2, PZP and IGLC3 were significantly upregulated compared with both cell types alone.…”

Daratumumab May Attenuate Cardiac Dysfunction Related to Carfilzomib in Patients with Relapsed/Refractory Multiple Myeloma: A Prospective Study

“…Interestingly, the administration of metformin may reverse these carfilzomib-related cardiotoxic effects [48]. In a multi-omics integrative analysis, a downregulation of pyruvate along with an upregulation of lactate dehydrogenase B was detected in patients receiving carfilzomib who presented with CVAEs [49]. Furthermore, carfilzomib increases the expression of NF-κB, caspase-3, ERK and JNK, as well as the levels of malondialdehyde in cardiac cells, whereas it reduces the levels of cardiac glutathione and catalase enzyme activity [50].…”

Cardiovascular Toxicity of Antineoplastic Treatments in Hematological Diseases: Focus on Molecular Mechanisms to Improve Therapeutic Management

“…In addition, it downregulates the expression of genes involved in extracellular matrices, the integrin complex, cardiac contraction, as well as autophagy, and upregulates stress responsive proteins, including heat shock proteins [ 207 , 212 ]. Moreover, patients who have cardiovascular adverse events with carfilzomib, exhibited a down-regulation of pyruvate and the up-regulation of lactate dehydrogenase B, suggesting a potential role of the pyruvate oxidation pathway in mitochondrial dysfunction [ 213 ]. Carfilzomib also influences vascular smooth muscle cells, potentially exacerbating the vulnerability of atherosclerotic plaques [ 214 ].…”