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

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

Author information

1
College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
2
Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
3
Department of Pathology and Cell Biology, Columbia University, New York, NY, USA 10032, USA.
4
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
5
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
6
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
7
Department of Biomedical Informatics, Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10031, USA.
8
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
9
Yale Comprehensive Cancer Center, Yale School of Medicine, New Haven, CT 06510, USA.
10
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: carlos.cordon-cardo@mssm.edu.
11
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: josep.domingo-domenech@mssm.edu.

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.

PMID:
25670080
PMCID:
PMC4356948
DOI:
10.1016/j.ccell.2014.11.013
[Indexed for MEDLINE]
Free PMC Article

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