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

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

doi:10.1016/j.ccell.2017.09.003

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

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

Authors

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

Affiliations

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.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Androgen Antagonists / therapeutic use
Animals
Cell Differentiation
Cell Line, Tumor
Fibroblast Growth Factors / antagonists & inhibitors
Fibroblast Growth Factors / physiology*
Humans
Inhibitor of Differentiation Protein 1 / physiology
MAP Kinase Signaling System / drug effects
Male
Mice
Neoplasm Metastasis
Prostatic Neoplasms / drug therapy
Prostatic Neoplasms / pathology*
Receptors, Androgen / physiology*
Receptors, Fibroblast Growth Factor / antagonists & inhibitors
Receptors, Fibroblast Growth Factor / physiology
Signal Transduction / physiology*

Substances

Androgen Antagonists
ID1 protein, human
Inhibitor of Differentiation Protein 1
Receptors, Androgen
Receptors, Fibroblast Growth Factor
Fibroblast Growth Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding