Epigenetic reprogramming: A key mechanism driving therapeutic resistance

Prostate cancer initiation, development and progression is driven by androgen receptor (AR) signaling. Androgen deprivation therapy is the primary treatment for patients that present with locally advanced or metastatic disease. However, androgen deprivation therapy is not curative, and patients will...

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Bibliographic Details
Published in:Urologic oncology 2018-08, Vol.36 (8), p.375-379
Main Authors: Sheahan, Anjali V., Ellis, Leigh
Format: Article
Language:English
Subjects:
aggressive variant
CRPC
Disease Progression
Drug Resistance, Neoplasm - genetics
epigenetics
Epigenomics - methods
EZH2
Humans
Male
neuroendocrine
Prostatic Neoplasms, Castration-Resistant - genetics
Prostatic Neoplasms, Castration-Resistant - pathology
therapy
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Summary:Prostate cancer initiation, development and progression is driven by androgen receptor (AR) signaling. Androgen deprivation therapy is the primary treatment for patients that present with locally advanced or metastatic disease. However, androgen deprivation therapy is not curative, and patients will progress to castrate-resistant disease (CRPC). Although most patient’s progress to CRPC via restoration of AR signaling (CRPC-Ad), approximately a quarter of patients will progress via mechanisms independent of AR signaling. This highly lethal phenotype is termed aggressive variant prostate cancer (AVPC). Data from clinical and preclinical studies demonstrate that AVPC involves combinatorial loss-of-function mutations in key tumor suppressor genes, low to absent AR levels, and re-expression of reprogramming, stem, and neuroendocrine related gene signatures. Further, AVPC is shown to evolve from a CRPC-Ad phenotype. Overall, lineage plasticity underlying progression to AVPC is thought to be provoked by genome-wide chromatin remodeling. Here, we will discuss an emerging focus on key drivers of chromatin remodeling in AVPC, and how their identification could provide noninvasive biomarkers to predict or detect AVPC emergence, and therapeutic targets to prevent or reverse progression to AVPC.
ISSN:1078-1439
1873-2496
DOI:10.1016/j.urolonc.2017.12.021