Abstract 1356: Chromatin remodeler CHD7 drives lineage plasticity and chemoresistance in neuroendocrine prostate cancer.

Abstract Neuroendocrine prostate cancer (NEPC) is a lethal prostate carcinoma subtype that arises through neuroendocrine (NE) transdifferentiation in response to androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPIs). This process involves profound epigenetic and transcriptional reprogramming, causing loss of luminal features and acquisition of NE traits. Lineage-specific transcription factors (TFs), such as ASCL1, FOXA2, SOX2, and PROX1, have been implicated in orchestrating lineage transition. Critically, both the activation and functional engagement of these TFs depend on upstream chromatin remodeling, which dynamically shapes the chromatin landscape to facilitate lineage reprogramming. The significance of chromatin remodeling in NEPC is underscored by the characteristic “salt and pepper” nuclear morphology, reflecting extensive chromatin reorganization. Together, these molecular and histological features highlight chromatin remodelers as critical regulators of NEPC development and aggressiveness. However, the specific upstream remodelers remain poorly defined.Through integrated analysis of longitudinal RNA-seq data from the clinically relevant LTL331/331R PDX model, which captures the complete temporal progression from adenocarcinoma to castration-induced NEPC, we identified CHD7 as a key chromatin remodeler that is upregulated early during NEPC development, with its expression preceding NE trait acquisition and further increasing in terminal NEPC. Functional studies demonstrated that CHD7 overexpression facilitates NE transdifferentiation of adenocarcinoma cells under AR signaling suppression, while knockdown (KD) in NEPC cells reduces DNA synthesis and cell survival, increases apoptosis, and suppresses NE markers and key NE-TFs. RNA-seq analysis of CHD7-KD cells revealed downregulation of pathways governing NE differentiation, cell cycle progression, and DNA damage response (DDR), further supporting CHD7 in regulating NE-lineage commitment and maintaining genomic stability of NEPC cells. Additionally, CHD7 ChIP-seq and ATAC-seq analysis revealed direct binding and regulating accessibility of regulatory elements of these NE-TFs, supporting its upstream regulatory role in NEPC. Notably, we uncovered that CHD7 modulates replication stress via regulating the ATR-CHEK1 axis. CHD7-KD impairs CHEK1 phosphorylation at key activation sites, leading to DNA damage accumulation and heightened sensitivity to genotoxic stress. Therapeutically, CHD7-KD cells show increased cisplatin susceptibility and pharmacological inhibition of CHEK1 synergistically enhances cisplatin-induced cell death, suggesting that exploiting the CHD7-dependent CHEK1 axis could potentiate cisplatin-based combination therapy in NEPC. Citation Format: Mingchen Shi, Dong Lin, Xinyao Pang, Hui Xue, Xin Dong, Rebecca Wu, Adam Classen, Yuchao Ni, Zoe Maylin, Wei Dong, Xinpei Ci, Yong Wang, Yu Wang, Junru Chen, Ning Kang, Xiaojia Niu, Liangliang Liu, Vickie Wang, Martin E. Gleave, Colin Collins, Christopher J. Ong, Gang Wang, Yuzhuo Wang. Chromatin remodeler CHD7 drives lineage plasticity and chemoresistance in neuroendocrine prostate cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1356.