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.

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