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

Lookup NU author(s): Dr Ruth Rodriguez Barrueco

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).

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.

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Author(s): Vidal SJ, Rodriguez-Bravo V, Quinn SA, Rodriguez-Barrueco R, Lujambio A, Williams E, Sun X, delaIglesia-Vicente J, Lee A, Readhead B, Chen X, Galsky M, Esteve B, Petrylak DP, Dudley JT, Rabadan R, Silva JM, Hoshida Y, Lowe SW, Cordon-Cardo C, Domingo-Domenech J

Publication type: Article

Publication status: Published

Journal: Cancer Cell

Year: 2015

Volume: 27

Issue: 2

Pages: 223-239

Print publication date: 09/02/2015

Online publication date: 09/02/2015

Acceptance date: 13/11/2014

Date deposited: 18/07/2016

ISSN (print): 1535-6108

ISSN (electronic): 1878-3686

Publisher: Cell Press

URL: http://dx.doi.org/10.1016/j.ccell.2014.11.013

DOI: 10.1016/j.ccell.2014.11.013

PubMed id: 25670080

Notes: Comment in Taxane resistance in prostate cancer mediated by AR-independent GATA2 regulation of IGF2.

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