SOX2 promotes lineage plasticity and antiandrogen resistance in TP53-and RB1-deficient prostate cancer Academic Article uri icon


MeSH Major

  • Androgen Antagonists
  • Phenylthiohydantoin
  • Prostatic Neoplasms
  • Retinoblastoma Binding Proteins
  • SOXB1 Transcription Factors
  • Tumor Suppressor Protein p53
  • Ubiquitin-Protein Ligases


  • 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 date

  • January 6, 2017



  • Academic Article



  • eng

PubMed Central ID

  • PMC5247742

Digital Object Identifier (DOI)

  • 10.1126/science.aah4307

PubMed ID

  • 28059768

Additional Document Info

start page

  • 84

end page

  • 88


  • 355


  • 6320