Abstract Body: Background/Hypothesis: Trametinib, a selective MEK1/2 inhibitor used in BRAF-mutant malignancies, improves cancer outcomes but can cause clinically significant cardiac dysfunction and heart failure. Although suppression of cardioprotective MEK/ERK signaling has been implicated in trametinib-induced cardiotoxicity, emerging evidence suggests a role for localized cardiac inflammation. We hypothesized that trametinib induces cardiac injury in part through activation of innate immune pathways, including type I interferon signaling.
Methods: Male wild-type C57BL/6J mice were randomized to vehicle or trametinib (3 mg/kg/day by oral gavage) for 7 days. Cardiac function was assessed by echocardiography, and pulmonary congestion was evaluated by wet/dry lung ratios at endpoint. Hearts were weighed and enzymatically digested for flow cytometric analysis of cardiac immune cell composition. Myocardial injury was assessed by TUNEL staining, and inflammatory signaling was evaluated by qPCR. Data were analyzed using Student’s t-test or ANOVA, with p<0.05 considered significant.
Results: Seven days of trametinib treatment caused a significant decline in cardiac function, with reduced ejection fraction versus vehicle controls (53.7 ± 2.36% vs 80.3 ± 6.6%, p<0.01), and increased pulmonary congestion, reflected by a higher wet/dry lung ratio (4.18 ± 0.5 vs 3.16 ± 0.9, p<0.05). Flow cytometry showed that trametinib significantly altered cardiac innate immune composition, including increased neutrophil infiltration and reduced cardiac macrophages, while lymphocyte populations were unchanged. Histologic analysis demonstrated increased TUNEL staining in trametinib-treated hearts, consistent with greater myocardial injury. Trametinib also increased transcription of type I interferon pathway components and downstream inflammatory cytokines, including interferon-responsive genes and chemokines linked to immune cell recruitment.
Conclusions: Trametinib-induced cardiotoxicity is associated with impaired cardiac function, pulmonary congestion, myocardial injury, and marked remodeling of the cardiac innate immune response. These findings support a model in which trametinib triggers a type I interferon–associated inflammatory program that contributes to cardiac injury and identify innate immune signaling as a potential therapeutic target in cardio-oncology.