@article{20eb3b0d69f443c0b3f74111dfeda3fa,
title = "Androgen Receptor Pathway-Independent Prostate Cancer Is Sustained through FGF Signaling",
abstract = "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. Bluemn et al. show that androgen receptor (AR) inhibition results in a phenotypic shift in castration-resistant prostate cancer, leading to tumors that are AR-null but not neuroendocrine (NE). Models for AR-null, non-NE tumors show elevated FGF and MAPK activity and are sensitive to blockade of these pathways.",
keywords = "FGF, ID1, androgen-pathway independence, castration-resistant prostate cancer, neuroendocrine",
author = "Bluemn, {Eric G.} and Coleman, {Ilsa M.} and Lucas, {Jared M.} and Coleman, {Roger T.} and Susana Hernandez-Lopez and Robin Tharakan and Daniella Bianchi-Frias and Dumpit, {Ruth F.} and Arja Kaipainen and Corella, {Alexandra N.} and Yang, {Yu Chi} and Nyquist, {Michael D.} and Elahe Mostaghel and Hsieh, {Andrew C.} and Xiaotun Zhang and Eva Corey and Brown, {Lisha G.} and Nguyen, {Holly M.} and Kenneth Pienta and Michael Ittmann and Michael Schweizer and True, {Lawrence D.} and David Wise and Rennie, {Paul S.} and Vessella, {Robert L.} and Colm Morrissey and Nelson, {Peter S.}",
note = "Funding Information: We are grateful to the patients and their families who participated in this study. We thank members of the P.S.N. laboratory for helpful advice and criticism. We thank Steve Plymate for helpful advice and assistance with analyses. We thank the FHCRC Genomics shared resource for assistance with RNA-seq experiments. We would also like to thank Yoshito Nakanishi for his advice, Bryce Lakely and Belinda Nguyen for technical assistance, Celestia Higano, Bruce Montgomery, Evan Yu, Heather Cheng, Funda-Vakar Lopez, Martine Roudier, Kristine Von Maltzan, Maria Tretiakova, and the rapid autopsy teams in the Urology Department at the University of Washington for their contributions to the Prostate Cancer Donor Rapid Autopsy Program. This work was supported by NIH awards: Prostate SPORE grant P50CA097186 , P01 CA163227 , DOD awards PC140794 and PC160662 , a DF/HCC Mazzone award, the Institute for Prostate Cancer Research , the Richard M. Lucas Foundation , and a Challenge award from Movember and the Prostate Cancer Foundation . Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = oct,
day = "9",
doi = "10.1016/j.ccell.2017.09.003",
language = "English (US)",
volume = "32",
pages = "474--489.e6",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "4",
}