SOX2 Promotes Lineage Plasticity and Antiandrogen Resistance in TP53- And RB1-deficient Prostate Cancer

Science. 2017 Jan 6;355(6320):84-88. doi: 10.1126/science.aah4307.

Abstract

Some cancers evade targeted therapies through a mechanism known as lineage plasticity, whereby tumor cells acquire phenotypic characteristics of a cell lineage whose survival no longer depends on the drug target. We use in vitro and in vivo human prostate cancer models to show that these tumors can develop resistance to the antiandrogen drug enzalutamide by a phenotypic shift from androgen receptor (AR)-dependent luminal epithelial cells to AR-independent basal-like cells. This lineage plasticity is enabled by the loss of TP53 and RB1 function, is mediated by increased expression of the reprogramming transcription factor SOX2, and can be reversed by restoring TP53 and RB1 function or by inhibiting SOX2 expression. Thus, mutations in tumor suppressor genes can create a state of increased cellular plasticity that, when challenged with antiandrogen therapy, promotes resistance through lineage switching.

Publication types

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

MeSH terms

  • Androgen Antagonists / therapeutic use*
  • Cell Line, Tumor
  • Cell Lineage
  • Cell Plasticity
  • Humans
  • Male
  • Phenylthiohydantoin / analogs & derivatives*
  • Phenylthiohydantoin / therapeutic use
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / pathology*
  • Retinoblastoma Binding Proteins / genetics*
  • SOXB1 Transcription Factors / genetics
  • SOXB1 Transcription Factors / metabolism*
  • Tumor Suppressor Protein p53 / genetics*
  • Ubiquitin-Protein Ligases / genetics*

Substances

  • Androgen Antagonists
  • MDV 3100
  • RB1 protein, human
  • Retinoblastoma Binding Proteins
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Phenylthiohydantoin
  • Ubiquitin-Protein Ligases