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

被引：115

作者：

Vidal, Samuel J. ^{[1
,2
]}

Rodriguez-Bravo, Veronica ^{[3
]}

Quinn, S. Aidan ^{[4
]}

Rodriguez-Barrueco, Ruth ^{[2
]}

Lujambio, Amaia ^{[5
]}

Williams, Estrelania ^{[2
]}

Sun, Xiaochen ^{[6
]}

de la Iglesia-Vicente, Janis ^{[2
]}

Lee, Albert ^{[7
]}

Readhead, Ben ^{[8
]}

Chen, Xintong ^{[6
]}

Galsky, Matthew ^{[6
]}

Esteve, Berta ^{[2
]}

Petrylak, Daniel P. ^{[9
]}

Dudley, Joel T. ^{[8
]}

Rabadan, Raul ^{[7
]}

Silva, Jose M. ^{[2
]}

Hoshida, Yujin ^{[6
]}

Lowe, Scott W. ^{[5
]}

Cordon-Cardo, Carlos ^{[2
]}

Domingo-Domenech, Josep ^{[2
]}

机构：

[1] Columbia Univ, Coll Phys & Surg, New York, NY 10032 USA

[2] Icahn Sch Med Mt Sinai, Dept Pathol, New York, NY 10029 USA

[3] Mem Sloan Kettering Canc Ctr, Program Mol Biol, New York, NY 10065 USA

[4] Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10032 USA

[5] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA

[6] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA

[7] Columbia Univ, Ctr Computat Biol & Bioinformat, Dept Biomed Informat, New York, NY 10031 USA

[8] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA

[9] Yale Univ, Sch Med, Yale Comprehens Canc Ctr, New Haven, CT 06510 USA

来源：

CANCER CELL | 2015年 / 27卷 / 02期

关键词：

GROWTH-FACTOR-II; ANDROGEN RECEPTOR; TRANSCRIPTION FACTORS; INCREASED SURVIVAL; GENE-EXPRESSION; TUMOR-GROWTH; DOCETAXEL; IGF2; MITOXANTRONE; INHIBITION;

D O I：

10.1016/j.ccell.2014.11.013

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：223 / 239

页数：17

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