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Combined BET bromodomain and DNA methyltransferase inhibition targets critical survival pathways in

William K Storck1,2, Diana Flores1,2, Anbarasu Kumaraswamy1,2

  • 1Department of Internal Medicine.

JCI Insight
|August 11, 2026
PubMed

Insights

Loss of TP53 and RB1 in prostate cancer drives lineage plasticity, a resistance mechanism. Combined BET bromodomain and DNA methyltransferase inhibition shows promise for treating these aggressive tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Lineage plasticity, or transdifferentiation, is a key resistance mechanism to androgen receptor (AR) inhibition in prostate cancer.
  • This plasticity involves loss of AR signaling, epithelial differentiation, and activation of stemness, epithelial-mesenchymal transition (EMT), or neuroendocrine prostate cancer (NEPC) programs.
  • Loss of tumor suppressors TP53 and RB1 is frequent in lineage plasticity but the underlying mechanisms are unclear, limiting treatment options.

Purpose of the Study:

  • To investigate the molecular mechanisms by which TP53/RB1 loss promotes lineage plasticity in prostate cancer.
  • To identify potential therapeutic strategies targeting TP53/RB1-deficient prostate tumors exhibiting lineage plasticity.

Main Methods:

  • Multi-omic profiling (chromatin accessibility, DNA methylation, gene expression) of TP53/RB1 loss prostate cancer models.
  • Assessment of BET bromodomain inhibition on activated pathways.
  • Evaluation of combined BET bromodomain and DNA methyltransferase (DNMT) inhibition efficacy.

Main Results:

  • TP53/RB1 loss alters chromatin accessibility, DNA methylation, and gene expression, promoting lineage plasticity.
  • BET bromodomain inhibition can block key pathways activated by TP53/RB1 loss.
  • Widespread DNA methylation changes in TP53/RB1-deficient cells silence plasticity-restraining pathways.
  • Combined BET bromodomain and DNMT inhibition significantly suppressed tumor growth in models with stem-like or NEPC programs.

Conclusions:

  • TP53/RB1 loss facilitates prostate cancer lineage plasticity through epigenetic alterations.
  • Combined BET bromodomain and DNMT inhibition represents a promising therapeutic strategy for aggressive, lineage-plastic prostate cancers.
Keywords:
Cell biologyDrug therapyEpigeneticsOncologyProstate cancer

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