1. Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer
- Author
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Labrecque, Mark P., Coleman, Ilsa M., Brown, Lisha G., True, Lawrence D., Kollath, Lori, Lakely, Bryce, Nguyen, Holly M., Yang, Yu.C., da Costa, Rui M. Gil, Kaipainen, Arja, Coleman, Roger, Higano, Celestia S., Yu, Evan Y., Cheng, Heather H., Mostaghel, Elahe A., Montgomery, Bruce, Schweizer, Michael T., Hsieh, Andrew C., Lin, Daniel W., Corey, Eva, Nelson, Peter S., and Morrissey, Colm
- Subjects
Thermo Fisher Scientific Inc. ,Bayer AG ,Phenotypes -- Analysis -- Health aspects ,Enzalutamide -- Analysis -- Health aspects ,Abiraterone -- Analysis -- Health aspects ,Genes -- Analysis -- Health aspects ,Transcription (Genetics) -- Analysis -- Health aspects ,Medical research -- Analysis -- Health aspects ,Genomes -- Analysis -- Health aspects ,Genomics -- Analysis -- Health aspects ,RNA -- Analysis -- Health aspects ,Scientific equipment industry -- Analysis -- Health aspects ,Immunohistochemistry -- Analysis -- Health aspects ,RNA sequencing -- Analysis -- Health aspects ,Prostate cancer -- Genetic aspects -- Development and progression -- Analysis -- Health aspects ,Pharmaceutical industry -- Analysis -- Health aspects ,Cancer metastasis -- Genetic aspects -- Development and progression -- Analysis -- Health aspects ,Biochemistry ,Motor vehicle drivers ,Clinical trials ,Tumors ,Gene expression ,Health care industry ,University of Washington - 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 5 mCRPC phenotypes based on the expression of well-characterized androgen receptor (AR) or neuroendocrine (NE) genes: AR-high tumors (ARPC), AR-low tumors (ARLPC), amphicrine tumors composed of cells coexpressing AR and NE genes (AMPC), double-negative tumors (i.e., [AR.sup.-]/[NE.sup.-]; DNPC), and 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 5 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., Introduction The androgen receptor (AR) regulates cellular programs that promote the survival and proliferation of prostate cancer (PC) cells. Consequently, first-line treatment for metastatic PC centers on inhibiting AR activity [...]
- Published
- 2019
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