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Lineage plasticity is characterized by loss of AR signaling and epithelial differentiation, along with activation of stemness-associated pathways, epithelial-mesenchymal transition, or alternative differentiation programs such as neuroendocrine prostate cancer (NEPC). Loss of the tumor suppressors\n                    <jats:italic>TP53<\/jats:italic>\n                    and\n                    <jats:italic>RB1<\/jats:italic>\n                    is common in tumors exhibiting lineage plasticity; however, the mechanisms by which\n                    <jats:italic>TP53<\/jats:italic>\n                    \/\n                    <jats:italic>RB1<\/jats:italic>\n                    loss promotes this phenotype remain poorly understood, and effective treatments are limited. Using multiomic profiling of\n                    <jats:italic>TP53<\/jats:italic>\n                    \/\n                    <jats:italic>RB1<\/jats:italic>\n                    -loss prostate cancer models, we identified alterations in chromatin accessibility, DNA methylation, and gene expression associated with lineage plasticity. Importantly, many pathways activated upon\n                    <jats:italic>TP53<\/jats:italic>\n                    \/\n                    <jats:italic>RB1<\/jats:italic>\n                    loss could be blocked through BET bromodomain inhibition.\n                    <jats:italic>TP53<\/jats:italic>\n                    \/\n                    <jats:italic>RB1<\/jats:italic>\n                    -deficient cells also harbored widespread DNA methylation changes that silenced pathways linked with restraining lineage plasticity. Combined BET bromodomain and DNA methyltransferase (DNMT) inhibition was more effective than single-agent treatment in suppressing growth of\n                    <jats:italic>TP53<\/jats:italic>\n                    \/\n                    <jats:italic>RB1<\/jats:italic>\n                    -loss models exhibiting a stem-like or NEPC program. This was partly explained by abrogation of discrete lineage plasticity pathways modulated by each agent. Altogether, our work suggests combined BET bromodomain and DNMT inhibition is a promising therapeutic approach for prostate tumors exhibiting lineage plasticity.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.207543","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T16:00:18Z","timestamp":1786464018000},"source":"Crossref","is-referenced-by-count":0,"title":["Combined BET bromodomain and DNA methyltransferase inhibition targets critical survival pathways in transdifferentiated prostate cancer"],"prefix":"10.1172","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8100-9191","authenticated-orcid":true,"given":"William K.","family":"Storck","sequence":"first","affiliation":[{"name":"Department of Internal Medicine,"},{"name":"Rogel Cancer Center,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Flores","sequence":"additional","affiliation":[{"name":"Department of Internal 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