Snail promotes resistance to enzalutamide through regulation of androgen receptor activity in prostate cancer.
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2016-08-02
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Abstract
Treatment with androgen-targeted therapies can induce upregulation of epithelial plasticity pathways. Epithelial plasticity is known to be important for metastatic dissemination and therapeutic resistance. The goal of this study is to elucidate the functional consequence of induced epithelial plasticity on AR regulation during disease progression to identify factors important for treatment-resistant and metastatic prostate cancer. We pinpoint the epithelial plasticity transcription factor, Snail, at the nexus of enzalutamide resistance and prostate cancer metastasis both in preclinical models of prostate cancer and in patients. In patients, Snail expression is associated with Gleason 9-10 high-risk disease and is strongly overexpressed in metastases as compared to localized prostate cancer. Snail expression is also elevated in enzalutamide-resistant prostate cancer cells compared to enzalutamide-sensitive cells, and downregulation of Snail re-sensitizes enzalutamide-resistant cells to enzalutamide. While activation of Snail increases migration and invasion, it is also capable of promoting enzalutamide resistance in enzalutamide-sensitive cells. This Snail-mediated enzalutamide resistance is a consequence of increased full-length AR and AR-V7 expression and nuclear localization. Downregulation of either full-length AR or AR-V7 re-sensitizes cells to enzalutamide in the presence of Snail, thus connecting Snail-induced enzalutamide resistance directly to AR biology. Finally, we demonstrate that Snail is capable of mediating-resistance through AR even in the absence of AR-V7. These findings imply that increased Snail expression during progression to metastatic disease may prime cells for resistance to AR-targeted therapies by promoting AR activity in prostate cancer.
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Ware, Kathryn E, Jason A Somarelli, Daneen Schaeffer, Jing Li, Tian Zhang, Sally Park, Steven R Patierno, Jennifer Freedman, et al. (2016). Snail promotes resistance to enzalutamide through regulation of androgen receptor activity in prostate cancer. Oncotarget, 7(31). pp. 50507–50521. 10.18632/oncotarget.10476 Retrieved from https://hdl.handle.net/10161/15123.
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Scholars@Duke
Jason Andrew Somarelli
Tian Zhang
Steven Patierno
Patierno's current translational research interests are focused on the genomics molecular biology of cancer disparities, cancer biology, molecular pharmacology and targeted experimental therapeutics to control prostate, breast and lung tumor aggressiveness. He is an internationally recognized expert in cancer control, cancer causation and molecular carcinogenesis, which includes a broad spectrum of laboratory and population level research. Patierno is also actively engaged in cancer health disparities and healthcare delivery research focused on patient navigation, survivorship, community-based interventions, mHealth, implementation sciences, cancer care economics, and policy.
Jennifer Freedman
Wen Chi Foo
Andrew John Armstrong
I am a clinical and translational investigator focused on precision therapies and biomarkers in advanced prostate and other GU cancers. I oversee a large research team of clinical and lab based investigators focused on improving patient outcomes, preventing metastatic disease, and understanding the biology of aggressive prostate cancer. Some key themes:
1. Predictors of sensitivity and clinical efficacy of therapies in advanced prostate cancer
2. Novel designs of clinical trials and pharmacodynamic/translational studies in prostate, kidney, bladder cancer
3. Pre-operative models for drug development of novel agents in human testing in prostate cancer
4. Novel therapies and drug development for prostate, renal, bladder, and testicular cancer
5. Design of rational combination therapies in men with metastatic hormone-refractory prostate cancer
6. Developing prognostic and predictive models for progression and survival in metastatic prostate cancer
7. Examining surrogate markers of mortality in metastatic prostate cancer
8. Clear cell and non-clear cell renal cell carcinoma: natural history, sensitivity to novel agents including mTOR and VEGF inhibition
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