Abstract
Trametinib (Trm) is a highly selective inhibitor of the tyrosine kinases MEK1/2 used to treat patients with melanoma and non-small cell lung cancer featuring BRAF mutations. Although Trm is generally well tolerated, it is associated with adverse cardiovascular effects including heart failure. Furthermore, the mechanisms underlying this cardiotoxicity are unclear. Here, we assessed the hypothesis that Trm decreases oxidative phosphorylation in the mouse heart. Female FVB mice were treated with Trm (3 mg/kg/d) or vehicle (DMSO) via oral gavage (n = 10, each group). We assessed cardiac contractility on Day 0 and Day 7 using echocardiography. We then performed electron transport chain (ETC) enzyme assays in isolated cardiac mitochondria and RNA sequencing of cardiac tissue to assess ETC Complex I-IV enzyme activity and ETC transcript abundance, respectively. Additionally, we measured citrate synthase (CS) activity as a marker for mitochondrial abundance. Mice treated with Trm had decreased fractional shortening on Day 7 compared to Day 0 (Panel A, 47.7 ± 1.6% vs. 55.5 ± 0.8%, p < 0.001) (mean ± SEM), confirming the cardiotoxicity of our treatment model. Additionally, mice treated with Trm had increased lung weight to heart weight (LW/HW) ratios compared to vehicle controls (Panel B, 1.69 ± 0.11 vs. 1.39 ± 0.03, p = 0.01), indicating heart failure. Mice treated with Trm had decreased CS (7,235 ± 586 vs. 8,562 ± 192 nmol/mg/min, p = 0.024), Complex II (1,659 ± 207 vs. 2,239 ± 239, p = 0.04), and Complex IV (3,979 ± 460 vs. 5,576 ± 615, p = 0.03) activities with a trend towards decreased Complex III (2,703 ± 452 vs. 3,554 ± 434, p = 0.09) activity (Panel C). Mice treated with Trm had decreased transcript abundance of Complex I (41 of 43), Complex II (6 of 6), Complex III (8 of 8), and Complex IV (18 of 23) transcripts (Panel D). Gene Ontology cellular compartment analysis of transcriptomic data revealed that Trm treatment primarily alters abundance of transcripts related to the mitochondrion (Panel E, p adj = 3.2 x 10 -113 ). KEGG Pathway analysis revealed that oxidative phosphorylation was the most significantly altered process following Trm treatment (Panel F, p adj = 2.9 x 10 -27 ). Collectively, these findings suggest that Trm causes widespread decreases in ETC activity that may hinder cardiomyocyte oxidative phosphorylation and contractility.
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