The heterogeneity of prostate cancers lacking AR activity will require diverse treatment approaches

in Endocrine-Related Cancer
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  • 1 M Labrecque, Department of Urology, University of Washington School of Medicine, Seattle, United States
  • 2 J Alumkal, Department of Internal Medicine, University of Michigan, Ann Arbor, United States
  • 3 I Coleman, Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, United States
  • 4 P Nelson, Division of Human Biology and Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, United States
  • 5 C Morrissey, Department of Urology, University of Washington School of Medicine, Seattle, United States

Correspondence: Colm Morrissey, Email: cmorriss@uw.edu
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The use of androgen deprivation therapy and second line anti-androgens in prostate cancer has led to the emergence of tumors employing multiple androgen receptor (AR)-dependent and AR-independent mechanisms to resist AR targeted therapies in castration-resistant prostate cancer (CRPC). While the AR signaling axis remains the cornerstone for therapeutic development in CRPC, a clearer understanding of the heterogeneous biology of CRPC tumors is needed for inno-vative treatment strategies. In this review, we discuss the characteristics of CRPC tumors that lack AR activity and the temporal and spatial considerations for the conversion of an AR-dependent to an AR-independent tumor type. We describe the more prevalent treatment-emergent phenotypes aris-ing in the CRPC disease continuum, including amphicrine, AR-low, double-negative, neuroendo-crine and small cell phenotypes. We discuss the association between the loss of AR activity and tumor plasticity with a focus on the roles of transcription factors like SOX2, DNA methylation, alterna-tive splicing, and the activity of epigenetic modifiers like EZH2, BRD4, LSD1, and the nBAF complex in conversion to a neuroendocrine or small cell phenotype in CRPC. We hypothesize that only a subset of CRPC tumors have the propensity for tumor plasticity and conversion to the neuroendo-crine phenotype and outline how we might target these plastic and emergent phenotypes in CRPC. In conclusion, we assess the current and future avenues for treatment and determine that the heter-ogeneity of CRPCs lacking AR activity will require diverse treatment approaches.

 

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