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Cancer Cell. 2017 Oct 9;32(4):474-489.e6. doi: 10.1016/j.ccell.2017.09.003.

Androgen Receptor Pathway-Independent Prostate Cancer Is Sustained through FGF Signaling.

Author information

1
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.
2
Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Mailstop D4-100, 1100 Fairview Avenue N, Seattle, WA 98109-1024, USA.
3
Department of Urology, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA.
4
Johns Hopkins University, Baltimore, MD, USA.
5
Baylor College of Medicine, Houston, TX, USA.
6
Department of Medicine, University of Washington, Seattle, WA, USA.
7
Department of Pathology, University of Washington, Seattle, WA, USA.
8
Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
9
Vancouver Prostate Centre, Vancouver, BC, Canada.
10
Department of Urology, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA. Electronic address: cmorriss@uw.edu.
11
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: pnelson@fhcrc.org.

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.

KEYWORDS:

FGF; ID1; androgen-pathway independence; castration-resistant prostate cancer; neuroendocrine

PMID:
29017058
PMCID:
PMC5750052
DOI:
10.1016/j.ccell.2017.09.003
[Indexed for MEDLINE]
Free PMC Article

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