Chromatin Accessibility Landscape And Transcriptome Of Castration Resistant Prostate Cancers Reveals Novel Subtypes And Diverse Master Regulators

Castration-resistant prostate cancer (CRPC) is a heterogeneous disease with diverse drivers and mechanisms of resistance to androgen receptor (AR) therapy. We generated ATAC-seq and RNA-seq data for twenty-four metastatic human prostate cancer organoids and cell lines. Integration of chromatin accessibility profiles and transcriptomes revealed four subtypes: androgen-receptor(AR)-dependent, neuroendocrine, Wnt-dependent and epithelial mesenchymal transition (EMT). The transcriptomic signatures obtained from these four subtypes enable the classification of 100 metastatic prostate cancer patient samples from Institute Precision Medicine (IPM) and 270 published samples from SU2C study, revealing potential therapeutic vulnerabilities. Furthermore, using novel computational algorithms we constructed regulatory networks and identified the master regulators of each subtype. Currently we9re carrying out western blot and quantitative PCR to confirm the subtypes of all prostate cancer models we use, and using drug sensitivity test, CRISPR knockout and cell competition assay to validate the functions of candidates in each subtype. Our study has characterized global chromatin accessibility landscape and transcriptome in the largest number of metastatic prostate cancer models, which revealed novel subtypes and corresponding tumor drivers. Collectively, these organoids, cell lines and matching sequence data provide a resource to the community to study various CRPC models. The molecular classification and corresponding master regulators reveal new drug targets and could potentially guide future therapeutic studies. Citation Format: Fanying Tang, Chen Khuan Wong, Sandra Cohen, Cindy Lee, Minwei Liu, Rohan Bareja, Kenneth Eng, Shaham Beg, Loredana Puca, Cora Sternberg, Juan Miguel Mosquera, Himisha Beltran, Andrea Sboner, Yu Chen, Ekta Khurana. Chromatin accessibility landscape and transcriptome of castration resistant prostate cancers reveals novel subtypes and diverse master regulators [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5310.