The synergistic action of HDAC inhibitor with cisplatin impedes survival and proliferation of drug-tolerant persister in gastric and liver cancer cells

Acquired therapy resistance is a dynamic process associated with early epigenetic modifications reshaping gene transcription across multiple cellular pathways, ultimately giving rise to drug-tolerant persister (DTP) cells. Unraveling the mechanisms that sustain DTP cell survival and drive their evolution into stable drug-resistant cells (DRC) is crucial for developing targeted therapies. Cisplatin-tolerant and cisplatin-resistant models were established using liver and gastric cancer cell lines for the first time to explore these mechanisms. Our investigation centered on the distinct epigenetic landscapes of DTP and DRC cells following cisplatin exposure. RNA sequencing revealed that DTP cells exhibit downregulation of pathways involved in cell cycle regulation, DNA replication, transcription, and chromatin maintenance while upregulating those associated with cell-cell communication and cytokine signaling. Interestingly, these transcriptional changes revert in the DRC state, suggesting a high degree of plasticity during the DTP phase. Furthermore, DTP cells have elevated levels of heterochromatin markers, H3K9me3, H3K27me3, and HP1α, along with their methyltransferases, G9a and Ezh2. Knockdown studies and inhibition of the enzyme activity of these modifiers showed suppression of DTP cell emergence. Valproic acid (VPA), a phase III candidate, was further assessed in vivo, where its sequential administration with cisplatin significantly reduced tumor burden versus cisplatin alone. These findings highlight the therapeutic promise of targeting epigenetic modifications to pre-sensitize cancer cells to chemotherapy, thereby restricting the survival advantage of DTP cells.