A targetable GATA2-IGF2 axis confers aggressiveness in lethal prostate cancer

Cancer Cell. 2015 Feb 9;27(2):223-39. doi: 10.1016/j.ccell.2014.11.013.

Abstract

Elucidating the determinants of aggressiveness in lethal prostate cancer may stimulate therapeutic strategies that improve clinical outcomes. We used experimental models and clinical databases to identify GATA2 as a regulator of chemotherapy resistance and tumorigenicity in this context. Mechanistically, direct upregulation of the growth hormone IGF2 emerged as a mediator of the aggressive properties regulated by GATA2. IGF2 in turn activated IGF1R and INSR as well as a downstream polykinase program. The characterization of this axis prompted a combination strategy whereby dual IGF1R/INSR inhibition restored the efficacy of chemotherapy and improved survival in preclinical models. These studies reveal a GATA2-IGF2 aggressiveness axis in lethal prostate cancer and identify a therapeutic opportunity in this challenging disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Cell Proliferation
  • Drug Resistance, Neoplasm / genetics
  • GATA2 Transcription Factor / genetics*
  • Humans
  • Insulin-Like Growth Factor II / genetics
  • Male
  • Mice
  • Prostatic Neoplasms, Castration-Resistant / drug therapy*
  • Prostatic Neoplasms, Castration-Resistant / genetics*
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • Receptor, Insulin / genetics
  • Signal Transduction
  • Xenograft Model Antitumor Assays

Substances

  • Antigens, CD
  • GATA2 Transcription Factor
  • GATA2 protein, human
  • IGF2 protein, human
  • Insulin-Like Growth Factor II
  • INSR protein, human
  • Receptor, Insulin

Associated data

  • GEO/GSE58966