Dickkopf-1 Can Lead to Immune Evasion in Metastatic Castration-Resistant Prostate Cancer

作者：David R. Wise, Jeffrey A. Schneider, Joshua Armenia, Victor Adorno Febles, Bridget E. McLaughlin, Ryan Brennan, Katie L. Thoren, Wassim M. Abida, Karen Sandell Sfanos, Angelo M. De Marzo, Srinivasan Yegnasubramanian, Josef J. Fox, Michael Haas, Heidi Heath, Michael H. Kagey, Walter Newman, Cynthia A. Sirard, Martin Fleisher, Michael J. Morris, Yu Chen, Steven M. Larson, Michael C. Haffner, Peter S. Nelson, Nikolaus D. Schultz, Michael J. Garabedian, Howard I. Scher, Susan K. Logan, Charles L. Sawyers, for the International SU2C/PCF Prostate Cancer Dream Team · 发表于：JCO Precision Oncology · 年份：2020 · DOI：10.1200/po.20.00097 · 被引用次数：62 · 研究领域：Prostate Cancer Treatment and Research、Prostate Cancer Diagnosis and Treatment、Radiopharmaceutical Chemistry and Applications

PURPOSE Metastatic castration-resistant prostate cancer (mCRPC) with low androgen receptor (AR) and without neuroendocrine signaling, termed double-negative prostate cancer (DNPC), is increasingly prevalent in patients treated with AR signaling inhibitors and is in need of new biomarkers and therapeutic targets. METHODS Candidate genes enriched in DNPC were determined using differential gene expression analysis of discovery and validation cohorts of mCRPC biopsies. Laboratory studies were carried out in human mCRPC organoid cultures, prostate cancer (PCa) cell lines, and mouse xenograft models. Epigenetic studies were carried out in a rapid autopsy cohort. RESULTS Dickkopf-1 (DKK1) expression is increased in DNPC relative to prostate-specific antigen (PSA)–expressing mCRPC in the Stand Up to Cancer/Prostate Cancer Foundation discovery cohort (11.2 v 0.28 reads per kilobase per million mapped reads; q < 0.05; n = 117) and in the University of Washington/Fred Hutchinson Cancer Research Center cohort (9.2 v 0.99 fragments per kilobase of transcript per million mapped reads; P < .0001). DKK1 expression can be regulated by activated Wnt signaling in vitro and correlates with activating canonical Wnt signaling mutations and low PSA mRNA in mCRPC biopsies ( P < .05). DKK1 hypomethylation was associated with increased DKK1 mRNA expression (Pearson r = −0.66; P < .0001) in a rapid autopsy cohort (n = 7). DKK1-high mCRPC biopsies are infiltrated with significantly higher numbers of qui...