Abstract Body: Background: Vascular endothelial growth factor receptor (VEGFR)-targeted tyrosine kinase inhibitors (TKIs) are frequently associated with hypertension; however, the mechanistic underpinnings and incidence of non-hypertensive cardiovascular events associated with next-generation VEGFR-TKIs, such as cabozantinib (CAB), remain poorly characterized.
Objectives: To elucidate the mechanisms of CAB-induced cardiotoxicity utilizing in vitro cardiac models, corroborated by real-world clinical outcomes.
Methods: H9c2 cardiomyoblasts were exposed to CAB (4 nM – 4 µM) for up to 72 hours. Cytotoxicity and underlying molecular mechanisms were interrogated via viability, lactate dehydrogenase (LDH), apoptosis, reactive oxygen species (ROS), RNA sequencing, and high-content morphological profiling (cell painting). Concurrently, human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) treated with 4 µM CAB were evaluated for bioenergetic and mitochondrial integrity. Finally, a retrospective cohort study of solid-tumor patients treated with CAB at a major cancer center was conducted to estimate the incidence of cancer-therapeutic-related cardiac dysfunction (CTRCD) and major adverse cardiovascular events (MACE).
Results: High-content cell painting coupled with UMAP dimensionality reduction, revealed morphological segregation of CAB-treated H9c2 cells compared with DMSO controls. CAB exposure significantly decreased viability while elevating LDH release, apoptosis, and ROS. Transcriptomic profiling (RNA-seq) of H9c2 cells exposed to low-dose CAB demonstrated significant enrichment of pathways associated with extracellular matrix remodeling and cardiac dysfunction; notably, expression of critical structural (e.g., desmin) and calcium-handling (e.g., Na⁺/Ca²⁺ exchanger) genes were markedly dysregulated. In hiPSC-CMs, CAB profoundly impaired mitochondrial bioenergetics and elevated rates of apoptosis and necrosis. Clinically, beyond anticipated hypertension, patients receiving CAB exhibited CTRCD (31.2%), incident atrial fibrillation (14.3%) and heart failure (6.5%).
Conclusions: This translational investigation demonstrates that CAB confers a substantial, clinically significant risk for adverse cardiovascular events, specifically heart failure and arrhythmogenesis. Mechanistically, this cardiotoxicity is driven by profound mitochondrial impairment, oxidative stress, and the transcriptional dysregulation of cytoskeletal and calcium-handling networks.