Abstract IA21: AR is ablated: Now what? Targeting the double-negative phenotype
Authors: Morrissey Colm , Bluemn Eric G. , Coleman Ilsa M. , Lucas Jared M. , Coleman Roger T. , Tharakan Robin , Bianchi-Frias Daniella , Dumpit Ruth F. , Kaipainen Arja , Corella Alexandra N. , Yang Yu Chi , Nyquist Michael D. , Mostaghel Elahe , Zhang Xiaotun , Corey Eva , Brown Lisha G. , Nguyen Holly M. , Schweizer Michael , True Lawrence D. , Rennie Paul S. , Vessella Robert L. , Nelson Peter S. 
Published: February 2019

Abstract
Background/Introduction: Androgen receptor (AR) signaling is a distinctive feature of prostate cancer (PC) and represents the major therapeutic target for treating metastatic prostate cancer (mPC). Though highly effective, AR antagonism can produce tumors that bypass a functional requirement for AR, often through neuroendocrine (NE) transdifferentiation. Through the molecular assessment of mPCs over two decades, we find that a phenotypic shift has occurred in mPC with the emergence of an AR-null NE-null phenotype. We sought to identify drivers of these “double-negative” PCs (DNPC), with the ultimate objective of developing therapeutic strategies.
Methods: We used genome-wide profiling of copy number (array CGH), mutations (whole-exome sequencing-WES), and gene expression (RNA-seq) to compare the molecular landscapes of AR-active PC (ARPC), NEPC, and DNPC in tumors obtained from 84 consecutive men with mPC undergoing a rapid autopsy. We developed model systems including DNPC patient-derived xenografts (PDX) and cell lines that are devoid of AR activity and lack NE features. Using these models, we tested therapeutics hypothesized to inhibit the activity of pathways preferentially active in DNPC.
Results: In the era prior to the approval of the AR pathway antagonists enzalutamide and abiraterone, most CRPCs were ARPCs (85%) with rare NEPCs (10%) and rarer DNPCs (5%). In the contemporary era (2012-2016), we observed a shift in tumor phenotypes with a higher representation of DNPCs. Gene expression programs of the tumors classified by IHC supported these distinct subtypes. DNPCs did not exhibit GR activity or PI3K/AKT activation but were notable for high MAPK and FGF pathway activity. Models systems recapitulated these findings. FGFR antagonists differentially repressed the growth of DNPC tumors in vitro and in vivo.
Conclusions: Though the majority of mPCs that resist AR targeting retain AR signaling, an increasingly common subtype of mPC exhibits a DNPC phenotype. Our results indicate that at least a subset of these DNPCs are driven by FGF signaling and MAPK activation. Targeting the FGF axis may represent a therapeutic approach for those cancers resistant to AR-directed therapies and may circumvent treatment resistance if combined with initial AR pathway blockade.
Citation Format: Colm Morrissey, Eric G. Bluemn, Ilsa M. Coleman, Jared M. Lucas, Roger T. Coleman, Robin Tharakan, Daniella Bianchi-Frias, Ruth F. Dumpit, Arja Kaipainen, Alexandra N. Corella, Yu Chi Yang, Michael D. Nyquist, Elahe Mostaghel, Xiaotun Zhang, Eva Corey, Lisha G. Brown, Holly M. Nguyen, Michael Schweizer, Lawrence D. True, Paul S. Rennie, Robert L. Vessella, Peter S. Nelson. AR is ablated: Now what? Targeting the double-negative phenotype [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr IA21.