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 IttmannMichael Schweizer, Lawrence D. True, David Wise, Paul S. Rennie, Robert L. Vessella, Colm Morrissey, Peter S. Nelson

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)474-489.e6
JournalCancer cell
Volume32
Issue number4
DOIs
StatePublished - Oct 9 2017

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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