Abstract A058: Lineage plasticity is associated with an altered MAX cistrome through super-enhancer remodeling

Abstract

Abstract Background: Roughly 20% of late stage prostate cancer patients display a lineage conversion from typical androgen receptor (AR) driven castrate resistant prostate cancer (CRPC) to a particularly lethal neuroendocrine prostate cancer (NEPC) phenotype as a result of AR pathway inhibition (ARPI). Notably, the mutational landscape of CRPC and NEPC is quite similar, suggesting that epigenetic changes may guide this lineage conversion. Our objective was to explore changes in active epigenetic marks with a particular focus on super-enhancers (SEs) and identify factors that regulate these active regions during lineage plasticity. Methods: We performed ChIP-seq for H3K27ac, H3K4me3 and various TFs in our CRPC and ENZ resistant (ENZR) NEPC-like cell models. We leveraged publicly available H3K27ac data in cell lines as well as PDX models to validate our findings. RNA-seq was integrated with our ChIP-seq results to create a signature which we applied to patient data sets. GIGGLE analysis was used to identify candidate factors at SEs. Results: CRPC and NEPC showed similar active marks at promoters however, enhancer elements were significantly remodeled. We observed extensive remodeling of SEs in our ENZR model compared to CRPC and these unique regions showed greater H3K27ac signals in other ENZR models such as NCI-H660. SE linked genes are associated with stemness pathways and are strongly upregulated as a result of ARPI in vitro, and in vivo. Factor enrichment analysis of these regions showed enrichment for MAX and MYC family binding similar to small cell lung cancer cell lines. ChIPseq for MYC and MAX in our cell models revealed an expansion of MAX binding and contraction of MYC binding in our ENZR model compared to CRPC. In particular, we saw increased binding of MAX at plasticity SEs without MYC suggesting an interaction with MYCL or other factors since MYCN is not expressed in our models. Conclusions: This work improves our understanding of the epigenetic changes that occur during lineage plasticity and ARPI resistance. SE analysis in our models suggests that MAX may be activating these regions with MYCL or independently of the MYC family. MYCL expression is upregulated in NEPC and has higher expression than MYCN suggesting a potential role during lineage plasticity. Citation Format: Maxim Kobelev, Dwaipayan Ganguli, Takeshi Namekawa, Amina Talal, Joshua Scurll, Amina Zoubeidi. Lineage plasticity is associated with an altered MAX cistrome through super-enhancer remodeling [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A058.