Combined BET Bromodomain and DNMT Inhibition Targets Lineage Plasticity in Prostate Cancer [BETi_DNMTi_mouse_RNAseq]

Loss of the tumor suppressors TP53 and RB1 is common in tumors exhibiting lineage plasticity; however, mechanisms by which TP53/RB1 loss promotes this phenotype remain poorly understood, and effective treatments are limited. Thus we used multi-omic profiling of TP53/RB1 loss prostate cancer models to identify alterations in chromatin accessibility, DNA methylation, and gene expression associated with lineage plasticity.

BET bromodomain inhibitors previously were shown to block genes associated with lineage plasticity. We sought to determine whether they could block pathways activated upon TP53/RB1 loss as well. TP53/RB1-deficient cells also harbored widespread DNA methylation changes that silenced pathways linked with lineage plasticity, which we found could be reversed by DNA methyltransferase (DNMT) inhibitors.