Deciphering Transcriptomic Changes Underlying Cisplatin Induced Drug Tolerance and Resistance in Gastrointestinal Cancer Cells

Acquired therapeutic resistance involves dynamic epigenetic reprogramming that mediates through drug tolerant persister (DTP) cells. To investigate this transition, cisplatin tolerant and resistant models were developed using liver and gastric cancer cell lines. RNA sequencing revealed that DTP cells downregulate pathways related to cell cycle, DNA replication, and chromatin organization, while upregulating cytokine signaling and cell communication. These changes were reversed in drug-resistant cells (DRC), indicating transcriptional plasticity. Elevated heterochromatin markers (H3K9me3, H3K27me3, HP1alpha) and their methyltransferases (EHMT2, EZH2) were observed in DTPs. Epigenetic inhibitors, including valproic acid, effectively suppressed DTP emergence, with in vivo studies showing enhanced tumor suppression when combined with cisplatin. These findings underscore the potential of epigenetic targeting to overcome drug tolerance in gastrointestinal cancers.