Osimertinib-induced cardiotoxicity is driven by HDAC-dependent epigenetic repression and rescued by vorinostat
Year: 2026
Type: article
Abstract: Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), has improved outcomes in non-small cell lung cancer (NSCLC) patients harboring the T790M mutation; however, emerging clinical evidence indicates a 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 cardiac dysfunction, impaired hypertrophic remodeling, and increased markers of heart failure and fibrosis. Unbiased transcriptomic profiling revealed a 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 histones, and enhanced cardiomyocyte apoptosis via Bax/caspase-mediated pathways. There was 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 prosurvival 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 antitumor 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.
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,790
Awards: G1090745310, G1647067295, G2056304158, G2309906587, G3437335754, G3552170932, G3979542943, G402572677, Novel Mechanisms of Cardiac Function and Dysfunction, Investigating the role of fibroblast-specific Peizo1 in cardiac dysfunction post-myocardial infarction, G6913808315, G7091973078, The Significance of Fibroblast and myeloid-Specific PD-L1 in Cardiac Pathophysiology post ischemic injury, Signaling Mechanisms Governing Myocardial Fibrosis in Diseased Heart, G8140514492, G8811204616, G9000261759
OpenAlex ID: W7166868412