| Literature DB >> 29017058 |
Eric G Bluemn1, Ilsa M Coleman2, Jared M Lucas2, Roger T Coleman2, Susana Hernandez-Lopez2, Robin Tharakan2, Daniella Bianchi-Frias2, Ruth F Dumpit2, Arja Kaipainen2, Alexandra N Corella2, Yu Chi Yang2, Michael D Nyquist2, Elahe Mostaghel1, Andrew C Hsieh1, Xiaotun Zhang3, Eva Corey3, Lisha G Brown3, Holly M Nguyen3, Kenneth Pienta4, Michael Ittmann5, Michael Schweizer6, Lawrence D True7, David Wise8, Paul S Rennie9, Robert L Vessella3, Colm Morrissey10, Peter S Nelson11.
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.Entities:
Keywords: FGF; ID1; androgen-pathway independence; castration-resistant prostate cancer; neuroendocrine
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Year: 2017 PMID： 29017058 PMCID： PMC5750052 DOI： 10.1016/j.ccell.2017.09.003
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743