期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 129, 期 10, 页码 4492-4505出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI128212
关键词
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资金
- Department of Defense Idea Development Award [W81XWH-17-1-0414, W81XWH-17-1-0415, W81XWH-15-1-0430, PC170431]
- Pacific Northwest Prostate Cancer SPORE [P50CA97186]
- Department of Defense Prostate Cancer Biorepository Network [W81XWH-14-2-0183]
- Department of Defense Prostate Cancer Clinical Trials Consortium [W81XWH-15-2-0008]
- National Cancer Institute (NCI) [R01 CA230617, NCI P01 CA163227]
- Prostate Cancer Foundation
- AACR NextGen Transformative Cancer Research Grant
- Institute for Prostate Cancer Research
- Richard M. LUCAS Foundation
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(-)/NE-; 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.
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