Distinct DNA methylation patterns associated with treatment resistance in metastatic castration resistant prostate cancer

Abstract

Androgens are a major driver of prostate cancer (PCa) and continue to be a critical treatment target for advanced disease, which includes castration therapy and antiandrogens. However, resistance to these therapies leading to metastatic castration-resistant prostate cancer (mCRPC), and the emergence of treatment-induced neuroendocrine disease (tNEPC) remains an ongoing challenge. Instability of the DNA methylome is well established as a major hallmark of PCa development and progression. Therefore, investigating the dynamics of the methylation changes going from the castration sensitive to the tNEPC state would provide insights into novel mechanisms of resistance. Using an established xenograft model of CRPC, genome-wide methylation analysis was performed on cell lines representing various stages of PCa progression. We confirmed extensive methylation changes with the development of CRPC and tNEPC using this model. This included key genes and pathways associated with cellular differentiation and neurodevelopment. Combined analysis of methylation and gene expression changes further highlighted genes that could potentially serve as therapeutic targets. Furthermore, tNEPC-related methylation signals from this model were detectable in circulating cell free DNA (cfDNA) from mCRPC patients undergoing androgen-targeting therapies and were associated with a faster time to clinical progression. These potential biomarkers could help with identifying patients with aggressive disease.

Role of Epigenetic Therapy in the Modulation of Tumor Growth and Migration in Human Castration-Resistant Prostate Cancer Cells with Neuroendocrine Differentiation

“…On the contrary, AZA profoundly modified DNA methylation pattern, sustaining a pervasive hypomethylation of the genome. Pathways analysis on the list of DMPs identified several biological processes associated with NED in previous studies [2, 11, 27] such as neural functions and axonal guidance but also others involved in regulation of cell migration, proliferation, and apoptosis. In particular, the most enriched pathway was Wnt/β-catenin signaling.…”

“…The authors suggested that this DNA methylation remodeling was associated to transition to neuroendocrine PC subtype [2]. Accordingly, using a xenograft model of CRPC, Peter et al [27] demonstrated that DNA methylation progressively changes from the castration naïve state to the treatment-induced NED state. These epigenetic alterations were likely able to affect gene expression of genes related to neurodevelopmental and morphogenic pathways.…”

“…On the contrary, DNA methylation remodeling was associated to transition to neuroendocrine PC subtype [2]. Accordingly, using a xenograft model of CRPC, Peter et al [27] For each DMR, the table reports its genomic location, the name of the gene mapping in the DMR, the Benjamini Hochberg corrected p value of the MANOVA test and PubMed references resulted from the query "gene name AND prostate cancer or neuroendocrine (title/ abstract)." DMRs defined on the basis of the UCSC CpG island name and relation to UCSC CpG island information.…”

Androgen receptor genomic alterations and treatment resistance in metastatic prostate cancer

“…Methylation profiling of cfDNA is also showing promise in understanding epigenomic patterns in tumor cells contributing to ctDNA, and has promise for clinical detection of neuroendocrine prostate cancer. 111,112 Furthermore, exciting new data suggest that it will be possible to detect active histone modifications in cells contributing to ctDNA through chromatin immunoprecipitation of cell-free nucleosomes (cfChIP-seq), direct from patient plasma. 113 Advances in single-cell profiling technology are now also improving resolution of genomic alterations in CTCs.…”

“…Since nucleosome occupancy can be inferred using cfDNA whole genome sequencing, it is plausible that cfDNA profiling may eventually help predict AR activity in prostate cancer cells, and therefore better define the relevance of detecting synchronous AR genomic alterations. Methylation profiling of cfDNA is also showing promise in understanding epigenomic patterns in tumor cells contributing to ctDNA, and has promise for clinical detection of neuroendocrine prostate cancer 111,112 . Furthermore, exciting new data suggest that it will be possible to detect active histone modifications in cells contributing to ctDNA through chromatin immunoprecipitation of cell‐free nucleosomes (cfChIP‐seq), direct from patient plasma 113 .…”