BMP-7 treatment ameliorates ponatinib-induced inflammatory mechanisms and cardiac dysfunction
D Singla, J RolandoAbstract
Background
Ponatinib is a potent third-generation tyrosine kinase inhibitor (TKI) used to treat highly resistant forms of leukemia. Despite its therapeutic efficacy, multiple clinical trials have reported substantial cardiotoxic effects associated with ponatinib, significantly limiting its clinical utility and leaving many patients without safe treatment alternatives. The molecular mechanisms underlying ponatinib-induced cardiotoxicity, however, remain poorly understood. Bone Morphogenetic Protein-7 (BMP-7), an FDA-approved agent used for bone regeneration, has demonstrated cardioprotective properties across several disease models. Nevertheless, its potential role in mitigating ponatinib-induced cardiotoxicity has yet to be investigated.
Purpose
This study aims to elucidate the pathophysiological mechanisms underlying ponatinib-induced cardiotoxicity and to evaluate the therapeutic potential of BMP-7 as a protective intervention.
Methods
C57BL/6 (10 ± 2 weeks of age, n= 8/group, 4 male and 4 female) mice were administered saline (control), ponatinib (30 mg/kg/day with a cumulative dose of 420 mg/kg), and ponatinib+BMP-7(200 µg/kg/day with a cumulative dose of 600 µg//kg). 28 days after the initial injection, cardiac function was assessed by echocardiography. Following the functional evaluation, animals were euthanized, and heart tissue was harvested for further analysis. These analyses included immunohistochemistry, RT-PCR, western blotting, and various histological staining techniques.
Results
Hearts from ponatinib-treated animals showed a significant (p < 0.05) increase in monocyte infiltration, a shift toward pro-inflammatory M1 macrophage polarization, and elevated levels of pro-inflammatory cytokines. This was accompanied by activation of the HMGB1–TLR4-dependent inflammatory pyroptosis pathway. Further, upregulation of downstream mediators, including NLRP3, caspase-1, IL-1β, and IL-18, was observed. These cellular alterations lead to the activation of the pyroptosis executor GSDMD and subsequent cell death. Additionally, structural analysis further demonstrated cardiac hypertrophy and enhanced fibrosis, while echocardiography confirmed marked declines in cardiac function. In contrast, BMP-7 treatment significantly (p < 0.05) enhanced anti-inflammatory M2 macrophage polarization and reduced inflammatory mechanisms. BMP-7 also strongly suppressed the activation of the pyroptotic signaling cascade, preserving cardiac structure and function.
Conclusions
Our results uncover previously unrecognized pathways driving ponatinib-related cardiotoxicity, demonstrating that the drug triggers immune cell activation and inflammatory forms of cell death, which drive adverse structural remodeling and impaired cardiac function. Importantly, BMP-7 mitigates these damaging processes, indicating its promise as a therapeutic strategy to protect against ponatinib-induced cardiotoxicity in patients undergoing leukemia treatment.