Abstract 14056: The Role of Immune Activation in Trametinib-Induced Cardiomyopathy

Abstract

Introduction: Trametinib (Trm) is a highly selective inhibitor of MEK1/2, downstream targets of the RAS signaling pathway that has been used widely for the treatment of BRAF V600E/K-mutant melanoma. Multiple clinical trials are also underway investigating its use in colorectal, prostate cancer, leukemia, and triple negative breast cancer. Trm is generally well tolerated but can be associated with potentially serious cardiotoxicity in 5-20% of treated patients. The specific mechanisms driving Trm-induced cardiomyopathy (TIC) are largely unexplored. The goal of this project is to investigate the role that resident and infiltrating inflammatory cells play in TIC. Hypothesis: Our data suggest that Trm provokes cardiomyocyte immune responses including increased production of inflammatory cytokines, NF-KB signaling, and macrophage infiltration. We hypothesize that this activation occurs through DAMP-driven activation of the TLR and cGAS-STING pathway. Methods: C57BL/6 mice were gavaged with Trm 3mg/kg/day for 3 days prior to sacrifice. Heart tissue was analyzed via RNAseq, confocal microscopy, and flow cytometry. In vitro assays were completed using neonatal rat ventricular myocytes (NRVM). Results: RNAseq data of whole heart tissue from Trm treated mice surprisingly demonstrated increased expression of transcripts in inflammatory pathways. In vitro stimulation of NRVMs with Trm demonstrated increased production of inflammatory cytokines including IFNy and increased NF-KB signaling. Confocal microscopy of Trm treated heart tissue demonstrated increased CD68+ macrophage recruitment compared to control. None of these findings would have been predicted by our previous knowledge of cardiomyocyte MEK biology. Conclusions: Trm treatment is associated with cardiomyopathy in up to 20% of patients. Understanding the mechanisms driving this disease pathogenesis may help reduce likelihood of adverse cardiac events associated with future MEK inhibitor therapy used alone or in combination with other agents. Our novel findings suggest that Trm causes immune dysregulation and inflammation in the heart. Future studies will focus on further characterization of immune cell subsets involved and mechanisms of innate immune activation in TIC.