TY - JOUR
T1 - Suppression of Acquired Docetaxel Resistance in Prostate Cancer through Depletion of Notch- and Hedgehog-Dependent Tumor-Initiating Cells
AU - Domingo-Domenech, Josep
AU - Vidal, Samuel J.
AU - Rodriguez-Bravo, Veronica
AU - Castillo-Martin, Mireia
AU - Quinn, S. Aidan
AU - Rodriguez-Barrueco, Ruth
AU - Bonal, Dennis M.
AU - Charytonowicz, Elizabeth
AU - Gladoun, Nataliya
AU - de la Iglesia-Vicente, Janis
AU - Petrylak, Daniel P.
AU - Benson, Mitchell C.
AU - Silva, Jose M.
AU - Cordon-Cardo, Carlos
PY - 2012/9/11
Y1 - 2012/9/11
N2 - Acquired resistance to Docetaxel precedes fatality in hormone-refractory prostate cancer (HRPC). However, strategies that target Docetaxel resistant cells remain elusive. Using in vitro and in vivo models, we identified a subpopulation of cells that survive Docetaxel exposure. This subpopulation lacks differentiation markers and HLA class I (HLAI) antigens, while overexpressing the Notch and Hedgehog signaling pathways. These cells were found in prostate cancer tissues and were related to tumor aggressiveness and poor patient prognosis. Notably, targeting Notch and Hedgehog signaling depleted this population through inhibition of the survival molecules AKT and Bcl-2, suggesting a therapeutic strategy for abrogating Docetaxel resistance in HRPC. Finally, these cells exhibited potent tumor-initiating capacity, establishing a link between chemotherapy resistance and tumor progression.
AB - Acquired resistance to Docetaxel precedes fatality in hormone-refractory prostate cancer (HRPC). However, strategies that target Docetaxel resistant cells remain elusive. Using in vitro and in vivo models, we identified a subpopulation of cells that survive Docetaxel exposure. This subpopulation lacks differentiation markers and HLA class I (HLAI) antigens, while overexpressing the Notch and Hedgehog signaling pathways. These cells were found in prostate cancer tissues and were related to tumor aggressiveness and poor patient prognosis. Notably, targeting Notch and Hedgehog signaling depleted this population through inhibition of the survival molecules AKT and Bcl-2, suggesting a therapeutic strategy for abrogating Docetaxel resistance in HRPC. Finally, these cells exhibited potent tumor-initiating capacity, establishing a link between chemotherapy resistance and tumor progression.
UR - http://www.scopus.com/inward/record.url?scp=84866021276&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2012.07.016
DO - 10.1016/j.ccr.2012.07.016
M3 - Article
C2 - 22975379
AN - SCOPUS:84866021276
SN - 1535-6108
VL - 22
SP - 373
EP - 388
JO - Cancer Cell
JF - Cancer Cell
IS - 3
ER -