Androgen receptor (AR) signaling is a distinctive feature of prostate carcinoma (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 a phenotypic shift has occurred in mPC with the emergence of an AR-null NE-null phenotype. These "double-negative" PCs are notable for elevated FGF and MAPK pathway activity, which can bypass AR dependence. Pharmacological inhibitors of MAPK or FGFR repressed the growth of double-negative PCs in vitro and in vivo. Our results indicate that FGF/MAPK blockade may be particularly efficacious against mPCs with an AR-null phenotype.
Cancer cell. 2017 Oct 09 [Epub]
Eric G Bluemn, Ilsa M Coleman, Jared M Lucas, Roger T Coleman, Susana Hernandez-Lopez, Robin Tharakan, Daniella Bianchi-Frias, Ruth F Dumpit, Arja Kaipainen, Alexandra N Corella, Yu Chi Yang, Michael D Nyquist, Elahe Mostaghel, Andrew C Hsieh, Xiaotun Zhang, Eva Corey, Lisha G Brown, Holly M Nguyen, Kenneth Pienta, Michael Ittmann, Michael Schweizer, Lawrence D True, David Wise, Paul S Rennie, Robert L Vessella, Colm Morrissey, Peter S Nelson
Department of Medicine, University of Washington, Seattle, WA, USA; Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Mailstop D4-100, 1100 Fairview Avenue N, Seattle, WA 98109-1024, USA., Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Mailstop D4-100, 1100 Fairview Avenue N, Seattle, WA 98109-1024, USA., Department of Urology, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA., Johns Hopkins University, Baltimore, MD, USA., Baylor College of Medicine, Houston, TX, USA., Department of Medicine, University of Washington, Seattle, WA, USA., Department of Pathology, University of Washington, Seattle, WA, USA., Memorial Sloan-Kettering Cancer Center, New York, NY, USA., Vancouver Prostate Centre, Vancouver, BC, Canada., Department of Urology, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA. Electronic address: ., Department of Medicine, University of Washington, Seattle, WA, USA; Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Mailstop D4-100, 1100 Fairview Avenue N, Seattle, WA 98109-1024, USA; Department of Urology, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA; Department of Pathology, University of Washington, Seattle, WA, USA. Electronic address: .