Differential mRNA expression analysis of multiple human and mouse pancreatic cancer cells and tumors after DMSO, tazemetostat, RMC-6236, or the combination treatment.

Our study demonstrated that combined treatment with the EZH2 inhibitor tazemetostat and the KRAS inhibitor RMC-6236 significantly suppressed the growth of subcutaneous and orthotopic tumors. To investigates the transcriptional effects of combined EZH2 and KRAS inhibition in pancreatic cancer models, transcriptome profiling was performed in PSN1, SW1990, and KPC cells treated with DMSO, tazemetostat, RMC-6236, or the combination of both inhibitors. In parallel, orthotopic KPC tumors subjected to the same treatments were harvested for RNA sequencing. In addition, an acquired resistance model to RMC-6236 was established in mice, and tumors treated with RMC-6236 alone or in combination with tazemetostat were collected at different stages for RNA-seq analysis to characterize dynamic changes in gene expression profiles. Overall design: For RNA-seq of combination treated cell lines, cells were treated with DMSO, tazemetostat, RMC-6236, or the combination treatment. For RNA-seq of combination treated orthotopic xenograft, tumor bearing mice were treated with vehicle, tazemetostat, RMC-6236, or the combination treatment. For RNA-seq of RMC-6236 acquired resistance mice model, tumor-bearing mice were initially treated with vehicle or RMC-6236 for 22 days. Mice receiving RMC-6236 were then further divided into an RMC-6236 monotherapy group or a combination therapy group receiving RMC-6236 together with an EZH2 inhibitor.