Cancer Therapeutic TKI Osimertinib-induced Cardiotoxicity Is Driven by HDAC-Dependent Epigenetic Repression and Rescued by Vorinostat

Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), has significantly improved outcomes in non–small cell lung cancer (NSCLC) patients harboring the T790M mutation; however, emerging clinical evidence indicates a substantial risk of cardiotoxicity. Here, we establish the first in vivo preclinical model of osimertinib-induced cardiotoxicity using transverse aortic constriction (TAC) in mice. Osimertinib treatment resulted in profound cardiac dysfunction, impaired hypertrophic remodeling, and increased markers of heart failure and fibrosis. Unbiased transcriptomic profiling revealed a maladaptive myocardial stress response characterized by activation of p53-associated cell death pathways, mitochondrial dysfunction, and negative enrichment of histone acetyltransferase (HAT) complexes, indicating epigenetic repression. Mechanistically, osimertinib-treated hearts exhibited increased expression of multiple histone deacetylase (HDAC) isoforms, reduced acetylation of key histones, and enhanced cardiomyocyte apoptosis via Bax/caspase-mediated pathways. There was only a minimal, transient effect on inflammation, supporting a type I, cell-autonomous cardiotoxic mechanism. Consistent with this, in vitro and in vivo analyses demonstrated suppression of pro-survival ERK/AKT signaling, mitochondrial dysfunction, and activation of intrinsic apoptotic pathways. Given the central role of HDAC activation, we tested whether pharmacologic HDAC inhibition could mitigate osimertinib-induced cardiotoxicity. Treatment with the FDA-approved HDAC inhibitor vorinostat (SAHA) restored histone acetylation, attenuated p53 activation, reduced cardiomyocyte death, and rescued cardiac function in osimertinib-treated mice. Translational studies in human NSCLC-derived PC9 cells further demonstrated that SAHA enhances osimertinib anti-tumor efficacy while alleviating cardiotoxicity. Collectively, these findings define HDAC-dependent epigenetic repression as a key mechanism underlying osimertinib-induced cardiotoxicity and identify HDAC inhibition as a therapeutically actionable strategy to improve both cardiac safety and cancer treatment efficacy.