Identifying Androgen Receptor-Independent Mechanisms of Prostate Cancer Resistance to Second-Generation Antiandrogen Therapy
Technical Report,01 Aug 2015,31 Jul 2017
Memorial Sloan Kettering Institute for Cancer Research New York United States
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We hypothesize that GR mediates resistance to enzalutamide in advanced prostate cancer through transactivation of SGK1 and activation of a non-luminal gene expression program. In this proposal, we aim to further explore the relationship between GR, SGK1, and enzalutamide resistance through experimental manipulation of GR and SGK1 in our previously reported laboratory models of enzalutamide resistance. In this research period, we engineered a CRISPR-mediated SGK1 deletion model of enzalutamide-resistant prostate cancer and observed modest reduction in tumor growth in response to enzalutamide. Our observation that SGK1 correlates with loss of AR signaling and EMT directly led us to the discovery that the immunomodulatory Wnt regulated cytokine,DKK1, is upregulated in AR-independent prostate cancer. We are currently validating whether DKK1 can be a useful biomarker and therapeutic target of this disease subtype.
- Medicine and Medical Research