Targeting Glucocorticoid Metabolism in Prostate Cancer

In the treatment of metastatic prostate cancer, resistance to hormonal therapy is a major obstacle. With antiandrogen therapies that suppress androgen signaling through the androgen receptor (AR), the primary driver of prostate cancer, some malignancies are able take advantage of the closely related glucocorticoid receptor (GR). Escape from AR dependency often involves a simple functional switch from 1 steroid receptor to another. Recent research efforts have outlined the mechanism enabling this switch, which involves alterations in glucocorticoid metabolism that occur with antiandrogen therapy to increase tumor tissue glucocorticoids and enable GR signaling. Targeting this mechanism pharmacologically by blocking hexose-6-phosphate dehydrogenase shows promise in normalizing glucocorticoid metabolism and restoring responsiveness to antiandrogen therapy. This perspective reviews what we have learned about this resistance mechanism, examines potential implications, and considers how this knowledge might be harnessed for therapeutic benefit.