Resistance to AR signaling inhibitors (ARSi) in a subset of metastatic castration-resistant prostate cancers (mCRPC) occurs with emergence of AR-negative Neuroendocrine Prostate Cancer (NEPC), coupled with mutations/deletions in PTEN, TP53, RB1, and overexpression of DNMTs, EZH2, and/or SOX2. To resolve whether lack of AR is the driving factor for the emergence of the NE phenotype, molecular, cell, and tumor biology analyses were performed on 23 prostate cancer patient-derived xenografts recapitulating the full spectrum of genetic alterations proposed to drive NE differentiation. Additionally, phenotypic response to CRISPR-Cas9-mediated AR knockout in AR-positive CRPC cells was evaluated. These analyses document that: 1) ARSi-resistant NEPC can develop without androgen deprivation treatment; 2) AR signaling in ARSi-resistant AR+/NE+ double positive "amphicrine" mCRPCs does not suppress NE differentiation; 3) lack of AR expression does not necessitate acquiring a NE phenotype despite concomitant mutations/deletions in PTEN and TP53, and loss of RB1, but can occur via emergence of an AR-/NE- double negative prostate cancer (DNPC); 4) despite DNPC cells having homogeneous genetic driver mutations, they are phenotypically heterogeneous, expressing basal lineage markers alone or in combination with luminal lineage markers; and 5) AR loss is associated with AR promoter hypermethylation in NEPCs but not in DNPCs.
JCI insight. 2021 Mar 16 [Epub ahead of print]
W Nathaniel Brennen, Yezi Zhu, Ilsa M Coleman, Susan L Dalrymple, Lizamma Antony, Radhika A Patel, Brian Hanratty, Roshan Chikarmane, Alan K Meeker, S Lilly Zheng, Jody E Hooper, Jun Luo, Angelo M De Marzo, Eva Corey, Jianfeng Xu, Srinivasan Yegnasubramanian, Michael C Haffner, Peter S Nelson, William G Nelson, William B Isaacs, John T Isaacs
Department of Urology, John Hopkins University School of Medicine, Baltimore, United States of America., Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, United States of America., Department of Oncology, Johns Hopkins University, Baltimore, United States of America., Department of Pathology, Johns Hopkins University, Baltimore, United States of America., Translational Research, North Shore University Health System, Evanston, United States of America., Department of Urology, University of Washington, Seattle, United States of America., Department of Pathology, University of Washington, Seattle, United States of America., Department of Nephrology, University of Washington, Seattle, United States of America.