2. Academic Validation
  3. Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer

Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer

  • J Clin Invest. 2019 Jul 30;129(10):4492-4505. doi: 10.1172/JCI128212.
Mark P Labrecque 1,  Ilsa M Coleman 2 3,  Lisha G Brown 1,  Lawrence D True 4,  Lori Kollath 1,  Bryce Lakely 1,  Holly M Nguyen 1,  Yu C Yang 2 3,  Rui M Gil da Costa 2 3,  Arja Kaipainen 2 3,  Roger Coleman 2 3,  Celestia S Higano 1 5,  Evan Y Yu 3 5,  Heather H Cheng 3 5,  Elahe A Mostaghel 5 6,  Bruce Montgomery 5 6,  Michael T Schweizer 3 5,  Andrew C Hsieh 2 3 5,  Daniel W Lin 1 7,  Eva Corey 1,  Peter S Nelson 2 3 5,  Colm Morrissey 1
Affiliations

Affiliations

  • 1 Department of Urology, University of Washington, Seattle, Washington, USA.
  • 2 Divison of Human Biology and.
  • 3 Divison of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
  • 4 Department of Pathology and.
  • 5 Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, Washington, USA.
  • 6 Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA.
  • 7 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
PMID: 31361600 DOI: 10.1172/JCI128212
Abstract

Metastatic castration-resistant prostate Cancer (mCRPC) is a heterogeneous disease with diverse drivers of disease progression and mechanisms of therapeutic resistance. We conducted deep phenotypic characterization of CRPC metastases and patient-derived xenograft (PDX) lines using whole genome RNA sequencing, gene set enrichment analysis and immunohistochemistry. Our analyses revealed five mCRPC phenotypes based on the expression of well-characterized Androgen Receptor (AR) or neuroendocrine (NE) genes: (i) AR-high tumors (ARPC), (ii) AR-low tumors (ARLPC), (iii) amphicrine tumors composed of cells co-expressing AR and NE genes (AMPC), (iv) double-negative tumors (i.e. AR-/NE-; DNPC) and (v) tumors with small cell or NE gene expression without AR activity (SCNPC). RE1-silencing transcription factor (REST) activity, which suppresses NE gene expression, was lost in AMPC and SCNPC PDX models. However, knockdown of REST in cell lines revealed that attenuated REST activity drives the AMPC phenotype but is not sufficient for SCNPC conversion. We also identified a subtype of DNPC tumors with squamous differentiation and generated an encompassing 26-gene transcriptional signature that distinguished the five mCRPC phenotypes. Together, our data highlight the central role of AR and REST in classifying treatment-resistant mCRPC phenotypes. These molecular classifications could potentially guide future therapeutic studies and clinical trial design.

Keywords

Cell Biology; Expression profiling; Molecular pathology; Oncology; Prostate cancer.

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