Androgen receptor pathway-independent prostate cancer is sustained through FGF signaling Journal Article


Authors: Bluemn, E. G.; Coleman, I. M.; Lucas, J. M.; Coleman, R. T.; Hernandez-Lopez, S.; Tharakan, R.; Bianchi-Frias, D.; Dumpit, R. F.; Kaipainen, A.; Corella, A. N.; Yang, Y. C.; Nyquist, M. D.; Mostaghel, E.; Hsieh, A. C.; Zhang, X.; Corey, E.; Brown, L. G.; Nguyen, H. M.; Pienta, K.; Ittmann, M.; Schweizer, M.; True, L. D.; Wise, D.; Rennie, P. S.; Vessella, R. L.; Morrissey, C.; Nelson, P. S.
Article 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. © 2017 Elsevier Inc.
Keywords: signal transduction; mitogen activated protein kinase; controlled study; human tissue; cancer growth; nonhuman; mouse; animal; animals; mice; animal tissue; metastasis; map kinase signaling system; inhibitor of differentiation 1; animal experiment; animal model; in vivo study; cell differentiation; in vitro study; pathology; enzyme activity; cell line, tumor; physiology; prostatic neoplasms; nucleotide sequence; tumor cell line; androgen antagonists; neoplasm metastasis; androgen receptor; inhibitor of differentiation protein 1; cancer tissue; antiandrogen; receptors, androgen; fibroblast growth factor; fibroblast growth factors; castration resistant prostate cancer; neuroendocrine; fgf; fibroblast growth factor receptor; id1; receptors, fibroblast growth factor; drug effects; castration-resistant prostate cancer; mapk signaling; humans; human; male; priority journal; article; id1 protein, human; lncap cell line; antagonists and inhibitors; androgen-pathway independence
Journal Title: Cancer Cell
Volume: 32
Issue: 4
ISSN: 1535-6108
Publisher: Cell Press  
Date Published: 2017-10-09
Start Page: 474
End Page: 489.e6
Language: English
DOI: 10.1016/j.ccell.2017.09.003
PUBMED: 29017058
PROVIDER: scopus
PMCID: PMC5750052
DOI/URL:
Notes: Article -- Export Date: 4 December 2017 -- Source: Scopus
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  1. David R Wise
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