A Targetable GATA2-IGF2 Axis Confers Aggressiveness in Lethal Prostate Cancer

Samuel J. Vidal, Veronica Rodriguez-Bravo, S. Aidan Quinn, Ruth Rodriguez-Barrueco, Amaia Lujambio, Estrelania Williams, Xiaochen Sun, Janis delaIglesia-Vicente, Albert Lee, Ben Readhead, Xintong Chen, Matthew Galsky, Berta Esteve, Daniel P. Petrylak, Joel T. Dudley, Raul Rabadan, Jose M. Silva, Yujin Hoshida, Scott W. Lowe, Carlos Cordon-CardoJosep Domingo-Domenech

Research output: Contribution to journalArticle

61 Scopus citations

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 byGATA2. 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.

Original languageEnglish (US)
Pages (from-to)223-239
Number of pages17
JournalCancer Cell
Volume27
Issue number2
DOIs
StatePublished - Feb 9 2015
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Vidal, S. J., Rodriguez-Bravo, V., Quinn, S. A., Rodriguez-Barrueco, R., Lujambio, A., Williams, E., Sun, X., delaIglesia-Vicente, J., Lee, A., Readhead, B., Chen, X., Galsky, M., Esteve, B., Petrylak, D. P., Dudley, J. T., Rabadan, R., Silva, J. M., Hoshida, Y., Lowe, S. W., ... Domingo-Domenech, J. (2015). A Targetable GATA2-IGF2 Axis Confers Aggressiveness in Lethal Prostate Cancer. Cancer Cell, 27(2), 223-239. https://doi.org/10.1016/j.ccell.2014.11.013