Suppression of Acquired Docetaxel Resistance in Prostate Cancer through Depletion of Notch- and Hedgehog-Dependent Tumor-Initiating Cells

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 lac...

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Bibliographic Details
Published in:Cancer cell 2012-09, Vol.22 (3), p.373-388
Main Authors: Domingo-Domenech, Josep, Vidal, Samuel J., Rodriguez-Bravo, Veronica, Castillo-Martin, Mireia, Quinn, S. Aidan, Rodriguez-Barrueco, Ruth, Bonal, Dennis M., Charytonowicz, Elizabeth, Gladoun, Nataliya, de la Iglesia-Vicente, Janis, Petrylak, Daniel P., Benson, Mitchell C., Silva, Jose M., Cordon-Cardo, Carlos
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Cell Line, Tumor
Disease Progression
Drug Resistance, Neoplasm
Hedgehog Proteins - genetics
Hedgehog Proteins - metabolism
Humans
Male
Mice
Mice, Inbred NOD
Mice, SCID
Molecular Sequence Data
Neoplastic Stem Cells - metabolism
Neoplastic Stem Cells - pathology
Prostatic Neoplasms - drug therapy
Prostatic Neoplasms - metabolism
Prostatic Neoplasms - pathology
Proto-Oncogene Proteins c-akt - antagonists & inhibitors
Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors
Receptors, Notch - genetics
Receptors, Notch - metabolism
Signal Transduction
Taxoids - pharmacology
Xenograft Model Antitumor Assays
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Summary: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. ► Docetaxel-resistant cells are undifferentiated and overexpress developmental pathways ► Docetaxel-resistant cells associate with poor clinical outcome in prostate cancer ► Notch and Hedgehog signaling inhibition depletes Docetaxel-resistant cells ► Docetaxel-resistant cells have high tumor-initiating capacity
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccr.2012.07.016