Myeloid cell leukemia 1 inhibition triggers a transient cardiac stress signature in a humanized mouse model

Background Myeloid cell leukemia-1 (MCL-1) is an essential anti-apoptotic protein and a promising therapeutic target in oncology. Despite encouraging anticancer efficacy, early clinical studies of MCL-1 inhibitors reported unexpected elevations in cardiac troponin, raising concerns about potential cardiotoxicity. Conventional murine models may incompletely capture human-relevant cardiac effects due to species-specific differences in MCL-1 pharmacology. Purpose Aim of this study is to investigate transcriptional consequences of MIK665-induced cardiotoxicity by deploying a specific mouse model with expression of the human MCL-1. Methods We investigated the cardiac effects of the selective MCL-1 inhibitor MIK665 in a humanized MCL-1 mouse model. Animals were treated once weekly and assessed for cardiac biomarkers, left ventricular function by echocardiography, and myocardial transcriptomic changes at peak treatment (Day 14) and after treatment cessation (Day 21). Bulk RNA sequencing was used to characterize differential gene expression, pathway enrichment, and higher-order transcriptional modules. Results MIK665 treatment induced a marked, time-dependent increase in circulating cardiac troponin T (hs-troponin T [pg/ml] on Day 14: 89 (54, 180) vs 1490 ± (998, 2425); placebo vs MIK665, shown as median (Q1, Q3), p< 0.001). Notably, and in line with clinical observation of patients treated with MCL1 inhibitor, this was not accompanied with a detectable impairment of left ventricular systolic function (EF [%] on Day 14: 78 ± (71, 88) vs 74 ± (72, 87); placebo vs MIK665, shown as median (Q1, Q3), p = 0.963). Transcriptomic analysis revealed coordinated suppression of mitochondrial, contractile, and translational gene programs during active treatment, accompanied by activation of stress- and immune-associated pathways. After treatment cessation, cardiac troponin levels declined and the myocardial transcriptome shifted toward a distinct recovery-associated profile characterized by epigenetic and cytoskeletal signaling pathways. Conclusion Pharmacological MCL-1 inhibition induces a reversible cardiac stress signature characterized by isolated troponin release and dynamic transcriptomic remodeling in the absence of overt systolic dysfunction. These findings provide mechanistic context for clinical cardiac biomarker signals observed with MCL-1 inhibitors and support the use of refined, humanized preclinical models to improve translational cardiac safety assessment.