ABSTRACT
Prostate cancer is heterogeneous and patients would benefit from methods that stratify those who are likely to respond to systemic therapy. Here, we employ single-cell assays for transposase-accessible chromatin (ATAC) and RNA sequencing in models of early treatment response and resistance to enzalutamide. In doing so, we identify pre-existing and treatment-persistent cell subpopulations that possess regenerative potential when subjected to treatment. We find distinct chromatin landscapes associated with enzalutamide treatment and resistance that are linked to alternative transcriptional programs. Transcriptional profiles characteristic of persistent cells are able to stratify the treatment response of patients. Ultimately, we show that defining changes in chromatin and gene expression in single-cell populations from pre-clinical models can reveal as yet unrecognized molecular predictors of treatment response. This suggests that the application of single-cell methods with high analytical resolution in pre-clinical models may powerfully inform clinical decision-making.
Subject(s)
Chromatin/chemistry , DNA, Neoplasm/genetics , Drug Resistance, Neoplasm/genetics , Neoplasm Proteins/genetics , Prostatic Neoplasms/genetics , Transcriptome , Antineoplastic Agents/therapeutic use , Benzamides/therapeutic use , Cell Line, Tumor , Chromatin/metabolism , DNA, Neoplasm/metabolism , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Male , Neoplasm Proteins/metabolism , Nitriles/therapeutic use , Phenylthiohydantoin/therapeutic use , Prostate/metabolism , Prostate/pathology , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/mortality , Prostatic Neoplasms/pathology , Sequence Analysis, RNA/methods , Single-Cell Analysis/methods , Survival Analysis , Exome SequencingABSTRACT
Prostate cancer (PCa) is among the most common adult malignancies, and the second leading cause of cancer-related death in men. As PCa is hormone dependent, blockade of the androgen receptor (AR) signaling is an effective therapeutic strategy for men with advanced metastatic disease. The discovery of enzalutamide, a compound that effectively blocks the AR axis and its clinical application has led to a significant improvement in survival time. However, the effect of enzalutamide is not permanent, and resistance to treatment ultimately leads to development of lethal disease, for which there currently is no cure. This review will focus on the molecular underpinnings of enzalutamide resistance, bridging the gap between the preclinical and clinical research on novel therapeutic strategies for combating this lethal stage of prostate cancer.
Subject(s)
Phenylthiohydantoin/analogs & derivatives , Benzamides , Drug Resistance, Neoplasm , Humans , Nitriles , Phenylthiohydantoin/pharmacology , Phenylthiohydantoin/therapeutic useABSTRACT
Ten-eleven translocation (TET) proteins are recently characterized dioxygenases that regulate demethylation by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine and further derivatives. The recent finding that 5hmC is also a stable and independent epigenetic modification indicates that these proteins play an important role in diverse physiological and pathological processes such as neural and tumor development. Both the genomic distribution of (hydroxy)methylation and the expression and activity of TET proteins are dysregulated in a wide range of cancers including prostate cancer. Up to now it is still unknown how changes in TET and 5(h)mC profiles are related to the pathogenesis of prostate cancer. In this review, we explore recent advances in the current understanding of how TET expression and function are regulated in development and cancer. Furthermore, we look at the impact on 5hmC in prostate cancer and the potential underlying mechanisms. Finally, we tried to summarize the latest techniques for detecting and quantifying global and locus-specific 5hmC levels of genomic DNA.
Subject(s)
DNA Methylation/genetics , Prostatic Neoplasms/genetics , Proto-Oncogene Proteins/metabolism , 5-Methylcytosine/analogs & derivatives , 5-Methylcytosine/metabolism , Animals , Epigenesis, Genetic , Humans , Male , Models, Biological , Proto-Oncogene Proteins/geneticsABSTRACT
Prostate cancer progression and treatment relapse is associated with changes in the androgen receptor axis, and analysis of alternations of androgen receptor signaling is valuable for prognostics and treatment optimization. The profile of androgen receptor axis is currently obtained from biopsy specimens, which are not always easy to obtain. Moreover, the information acquired only provides a snapshot of the tumor biology, with strict spatial and temporal limitations. On the other hand, circulation is easily accessible source of both circulating tumor cells and circulating tumor DNA, which can be sampled at numerous time points. This Review will explore the potential use of androgen receptor axis alternations detectable in the blood in therapeutic decision-making and precision medicine for advancing metastatic castration-resistant prostate cancer.
