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

Madonna R. Peter,Amina Zoubeidi,Misha Bilenky,Ruth Isserlin,Neil E. Fleshner,Gary D. Bader,Bharati Bapat,Martin Hirst,Alastair Davies

doi:10.1038/s41598-021-85812-3

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.

Highlights

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
We integrated our findings from this pre-clinical model with circulating cell free DNA from metastatic castration-resistant prostate cancer (mCRPC) patients to identify potential biomarkers associated with aggressive disease
When we examined the overlap between differentially methylated regions (DMRs) in cell free DNA (cfDNA) with CRPC-NE tissue related DMCs20, we found that patients that harbored a higher ratio of hypermethylated cfDNA DMRs to hypomethylated cfDNA DMRs (Visit A vs B) tended to demonstrate a faster time to clinical progression (TTP)[55]

Summary

Introduction

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. 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. Much focus in recent clinical trials is determining optimal therapy sequences at various stages of PCa, from the castration-naïve setting to the mCRPC s tate[9,10] While all of these treatments have been shown to improve survival, resistance occurs through various AR driven mechanisms and alternative lineage re-programming, owing to the molecular heterogeneity of PCa, which could lead to treatment induced neuroendocrine prostate cancer (tNEPC)[11,12,13]. We integrated our findings from this pre-clinical model with circulating cell free DNA (cfDNA) from mCRPC patients to identify potential biomarkers associated with aggressive disease

Methods

Results

Conclusion