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

GSE328472 Mus musculus (mouse) RNA-seq (gene expression) 10 samples Submitted 2026/05/29 Platform GPL34290
At a glance

RNA-seq (gene expression) · mouse · 10 samples

What it is
RNA-seq (gene expression)Gene activity measured by sequencing. The summary does not mention single-cell work, so this is most likely bulk: one average per sample, the usual starting point for comparing groups.
Organism
Mus musculus (mouse)
Samples
10 samples: 5 × Control-TAC Placebo vs 5 × Treatment-TAC OsimertinibGroups are read from the sample names, not from the paper. Check the list below.
Data you can get
A processed table (series matrix) and supplementary files from NCBI; the raw sequencing reads from ENA. Which of these hold counts depends on the study, so check the file list.
Summary (written by the submitters)
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.
Read the full summary ↓
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.
This dataset
Open GSE328472 in finder → Find more mouse RNA-seq datasets →
Download · which file do I need?

Direct links to NCBI and ENA, no account and no request form. Pick by what you want to do: take the small processed table to look, the supplementary files to re-analyse, or the original raw data to start over.

1 · Just have a look

Processed table

The series matrix: one table of values per sample as the submitters processed it. The smallest download, and it opens in Excel or R. Start here to see what the data look like.

Series matrix ↓
2 · Re-analyse it

Supplementary files

The count tables and other files the authors uploaded. Take only the samples you need, or the whole study as GSE328472_RAW.tar (it can run to tens of gigabytes).

All supplementary files ↗ Whole study · RAW.tar ↓
3 · Start from the raw reads

Raw sequencing reads

The original FASTQ files, straight from the sequencer, held at ENA. Large, and you align them yourself, so only choose this if you need to re-process the study from scratch.

Raw reads on ENA ↗

What the files usually look like: For RNA-seq the counts are usually a table among the supplementary files (look for 'counts', 'expression', 'FPKM' or 'TPM' in the file name). The series matrix of a sequencing study is sometimes nearly empty.

Also filed as BioProject PRJNA1455510 and SRA study SRP693140. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗
Study design
5 × Control-TAC Placebo vs 5 × Treatment-TAC Osimertinib

Supports a between-group comparison across 10 samples.

How we read this: 2 replicated groups read from 10 sample titles; they account for 10 of them. These groups are guessed from the sample names, not taken from the paper, so check them against the sample list below before relying on them.

Samples in this study
Datasets on a similar topic

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