Abstract 1456: Tumor lineage plasticity blockade by therapeutic targeting of an epigeneticregulator

Abstract Tumor lineage plasticity (LP) is an emerging hallmark of cancer progression in solidtumors, such as prostate cancer, pancreatic cancer and lung cancer. However, theexact molecular mechanisms that drive the aberrant LP programs remain poorlydefined. Here we identified bromodomain protein BRD4 as a crucial player. BRD4knockdown and its inhibitors potently suppressed the LP programs both in vitro and invivo. Integrated ChIP-seq and RNA-seq analysis of tumors revealed that BRD4 drivesLP by increasing local chromatin accessibility and directly activating LP gene programswhich includes neurogenesis, axonogenesis and stem cells and key drivers such asBRN2, ASCL1/2, SOX2, SOX9 and RUNX1/2. Significantly, we demonstrated thatBRD4 inhibitor AZD5153, currently at clinical development, possesses potent activity inalmost complete blockade of tumor growth of both de novo neuroendocrine prostatecancer (NEPC) and treatment-induced NEPC PDXs. Further study revealed thatsuppression of tumor expression of LP programs through reduction of local chromatinaccessibility is a primary mechanism of action (MOA) by AZD5153. Together, ourfindings demonstrated that BRD4 plays a fundamental role in directly activating tumorLP programs and that its inhibitor AZD5153 is highly promising in effective treatment ofthe lethal forms of the diseases. Citation Format: Xiong Zhang, Yatian Yang, Eva Corey, Hongwu Chen. Tumor lineage plasticity blockade by therapeutic targeting of an epigeneticregulator [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1456.