TY - JOUR
T1 - A Targetable GATA2-IGF2 Axis Confers Aggressiveness in Lethal Prostate Cancer
AU - Vidal, Samuel J.
AU - Rodriguez-Bravo, Veronica
AU - Quinn, S. Aidan
AU - Rodriguez-Barrueco, Ruth
AU - Lujambio, Amaia
AU - Williams, Estrelania
AU - Sun, Xiaochen
AU - delaIglesia-Vicente, Janis
AU - Lee, Albert
AU - Readhead, Ben
AU - Chen, Xintong
AU - Galsky, Matthew
AU - Esteve, Berta
AU - Petrylak, Daniel P.
AU - Dudley, Joel T.
AU - Rabadan, Raul
AU - Silva, Jose M.
AU - Hoshida, Yujin
AU - Lowe, Scott W.
AU - Cordon-Cardo, Carlos
AU - Domingo-Domenech, Josep
N1 - Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/2/9
Y1 - 2015/2/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84922788911&partnerID=8YFLogxK
U2 - 10.1016/j.ccell.2014.11.013
DO - 10.1016/j.ccell.2014.11.013
M3 - Article
C2 - 25670080
AN - SCOPUS:84922788911
SN - 1535-6108
VL - 27
SP - 223
EP - 239
JO - Cancer Cell
JF - Cancer Cell
IS - 2
ER -