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

作者：Vidal Samuel J; Rodriguez Bravo Veronica; Quinn S Aidan; Rodriguez Barrueco Ruth; Lujambio Amaia; Williams Estrelania; Sun Xiaochen; de la Iglesia Vicente Janis; Lee Albert; Readhead Ben; Chen Xintong; Galsky Matthew; Esteve Berta; Petrylak Daniel P; Dudley Joel T; Rabadan Raul; Silva Jose M; Hoshida Yujin; Lowe Scott W; Cordon Cardo Carlos^*; Domingo Domenech Josep

来源：Cancer Cell, 2015, 27(2): 223-239.

DOI：10.1016/j.ccell.2014.11.013

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.

• 出版日期2015-2-9