Abstract 3694: Differential expressions of miR-17 and complement factor D in carfilzomib-related cardiotoxicity in multiple myeloma patients: Results of microRNA array and proteomics integrated analysis

Abstract

Abstract Background: Carfilzomib (CFZ), a proteasome inhibitor used to treat multiple myeloma (MM), has been associated with risk for cardiotoxicity including heart failure (HF). There is a lack of data on the mechanism underlying CFZ-induced cardiotoxicity. Our study aims to better understand molecular mechanisms of CFZ-related cardiotoxicity by determining the differential expression of circulating miRNAs and proteins in MM patients. Methods: Plasma samples were collected from 13 MM patients after treated with CFZ (including 7 with cardiotoxicity and 6 with no cardiotoxicity) at the University of Florida Health Cancer Center. TaqMan OpenArray Human MicroRNA Panel containing 754 human miRNA was used for miRNA analysis, and iTRAQ analysis on LC/MS/MS platforms was used for global proteomic profiling. Results: The overall mean age was 61 and 38.5% were men. A total of 374 proteins were identified and 57 were differentially expressed between cardiotoxicity and non-cardiotoxicity groups (false discovery rate <0.05). Differential expression analysis of miRNAs profiling yielded 5 miRNAs that were dysregulated (p-value <0.05 and fold change (FC) < 0.5): miR-17, miR-30c, miR-30b, miR-106a, and miR-92a. Among the top proteins that differentiate the two groups were complement factor D (CFD) (P= 5.5*10-5, and FC= 6), which is targeted by miR-17. CFD circulates in an active form and cleaves complement factor B (FB) to Ba and Bb, which promote the alternative pathway complement (AP) activation, the complement activation has shown to occur in chronic HF, and is associated with adverse clinical events. Also, CFD has a function in the activation of notch signaling, which is required for the proliferation of cardiac stem cells and the survival of cardiomyocytes. Conclusion: These findings suggest that CFZ may induce cardiac dysfunction via increasing CFD activity that is regulated by miR-17, leading to activation of the complement system. Dysregulation in components of the AP of complement activation could impact the diastolic dysfunction associated with HF progression. Citation Format: Marwa Tantawy, Lakshmi Manasa Chekka, Taimour Langaee, Timothy J Garrett, Michael Fradley, Robert Frank Cornell, Rachid C. Baz, Sonal Singh, Lihui Yuan, Chintan P. Shah, Nida Waheed, Carl J. Pepine, Jan S. Moreb, Yan Gong. Differential expressions of miR-17 and complement factor D in carfilzomib-related cardiotoxicity in multiple myeloma patients: Results of microRNA array and proteomics integrated analysis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3694.