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

Lineage plasticity is increasingly recognized as a resistance mechanism to androgen receptor (AR) inhibition in prostate cancer. Neuroendocrine prostate cancer (NEPC) is the most lethal form of lineage plasticity in prostate cancer. BET bromodomain inhibitors (BETi) previously were shown to block genes associated with lineage plasticity. Extensive rewiring of DNA methylation is also associated with NEPC tumors. We sought to determine whether combined BET protein and DNA methyltransferase inhibition (DNMTi) would result in greater anti-tumor activity than single agent treatments alone. To test this, we treated NEPC cell line models with 500nM ZEN (BETi), 100nM dAZA (DNMTi), or the combination daily for 72hrs. We also tested the BETi + DNMTi combination in vivo using an NEPC PDX (LTL331R) with 50mg/kg ZEN and 0.8mg/kg dAZA. Combined BETi and DNMTi was more effective than single agent treatment in suppressing growth in NEPC models compared to single agent treatments. To identify the gene expression changes underlying the superior viability effect of the combo treatment, we peformed RNAseq on treated cells. We also performed RNAseq on a PDX model that reliably transitions from adenocarcinoma (LTL331) to NEPC (LTL331R) in order to uncover the gene expression changes associated with NEPC lineage plasticity and to determine whether BETi and/or DNMTi reverses these gene expression changes.