Background and Purpose:
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.
Methods: We investigated the cardiac effects of the selective MCL-1 inhibitor MIK665 in a humanised 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). To assess the effects of repeated MIK665 exposure, an additional long-term animal experiment was conducted using the same 21-day cycle treatment plan. Animals were sacrificed on day 14 of cycle 4. Bulk RNA sequencing was used to characterise differential gene expression, pathway enrichment, and higher-order transcriptional modules. Histological analysis was performed using Sirius red and Hematoxylin and Eosin staining.
Key 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) without 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). Cardiac fibrous tissue did not differ between groups at Day 14 or Day 21 (fibrous tissue [%] on Day 14: 7.63 (5.66, 8.93) vs 8.23 (6.12, 8.42); placebo vs MIK665, shown as median (Q1, Q3), p = 1.000). Transcriptomic analysis revealed coordinated suppression of mitochondrial, and contractile gene programs during active treatment, accompanied by activation of stress- and immune-associated pathways. However, a myocarditis-like injury or altered myocardial cellularity was not detected (myocardial cell density on Day 14: 5672 vs 6615; placebo vs MIK665, shown as median, p= 0.5368). After treatment cessation, cardiac troponin levels declined and the myocardial transcriptome shifted toward a distinct recovery-associated profile characterised by adaptive epigenetic and cytoskeletal signalling pathways.
Conclusions and Implications:
Pharmacological MCL-1 inhibition induced a cardiac biomarker and transcriptional stress response characterised by troponin release and dynamic myocardial transcriptomic remodelling. Additional functional and histological analyses did not reveal overt systolic dysfunction, strain-detectable impairment, or increased fibrotic remodelling within the investigated experimental settings. These alterations are consistent with a largely reversible cardiac stress response rather than overt structural or functional cardiotoxicity. These findings further support the use of refined, humanised preclinical models to improve translational cardiac safety assessment.
