SUO 2016: Mechanisms of Resistance to AR: AR Variants and GR - Session Highlights
San Antonio, Texas USA (UroToday.com) Dr. Arora presented original research demonstrating a new understanding of the resistance patterns to AR inhibition in castration-resistant metastatic prostate cancer (mCRPC).
Researchers at MSKCC and Washington University investigated ways in which resistant tumor cells appear to bypass AR signaling and make them resistant to targeted AR blockade with enzalutamide. They identified the active role that the glucocorticoid receptor (GR) played in this process. GR is able to functionally replace the activity of AR due to similar structural properties. Because of this, uninhibited GR is able to play the same role that AR plays in promoting cell proliferation. Worse, there appear to be subsets of cells that experience upregulation of GR after treatment with enzalutamide.
Using xenograft mouse models with different prostate cancer cell lines, researchers were able to characterize this GR upregulation in Enz-treated cells. AR pathways in normal cells appear to play a suppressive role with regard to GR expression. Investigators found that the GR enhancer/promoter region contains an AR binding motif, and enzalutamide exposure removes this AR suppression and therein induces GR expression. In summary, there is a loss of AR-mediated repression at the GR enhancer by enzalutamide treatment.
Additionally, there is another pathway (PRC2) that produces a molecule that binds to and inhibits the GR enhancer. It appears that GR induction may also require loss of this second inhibitory pathway in order to gain full expression. By replacing the small molecule (JQ1) within enzalutamide-resistant cells, researchers were able to restore enzalutamide sensitivity by blocking GR expression and avoiding the AR signaling bypass. There is currently a Phase I trial underway to evaluate this as a treatment modality.
The more we begin to understand the variant pathways that lead to resistant tumor cells, the more we will be able to identify drug targets that can intervene early. This is one example of a promising step in that direction.
Presented By: Vivek Arora, MD, Washington University
Written By: Shreyas Joshi, MD, Fox Chase Cancer Center
17th Annual Meeting of the Society of Urologic Oncology - November 30 -December 2, 2016 – San Antonio, Texas USA