Signaling Under Stress: Targeting the Glucocorticoid Receptor in Cancer

Glucocorticoid receptor (GR) signaling is critical to our physiology but is dysregulated in cancer by the pain, psychological distress, iatrogenic morbidity, and pathology associated with an advanced, invasive disease. Many tumors exploit glucocorticoid signaling to provide anti-apoptotic survival signals, stimulate growth and metastasis, suppress immune surveillance, and drive treatment resistance. Endogenous cortisol and exogenous glucocorticoids are typically associated with poor responses to cytotoxic chemotherapy, targeted therapy, and immunotherapy in patients with solid tumors. Translational and non-clinical data show that selective GR antagonists (SGRAs) synergize with anti-cancer agents, including taxanes, androgen receptor inhibitors, PARP inhibitors, and anti-PD(L)-1 immune checkpoint inhibitors, driving improved anti-cancer activity. In a tumor-intrinsic manner, SGRAs downregulate the anti-apoptotic proteins SGK1 and DUSP1, which induce resistance to cytotoxic chemotherapy. This synergy has been confirmed in several randomized controlled trials, which showed improved efficacy when SGRAs were added to standard-of-care taxane therapy in platinum-resistant ovarian cancer. In a distinct cellular context, SGRAs inhibit resistance to anti-androgen therapy mediated through the GR and have the potential for additive anti-cancer activity in prostate cancer. Herein, we summarize the role of glucocorticoid signaling in solid tumor biology, providing mechanistic insights into recent clinical advances and emphasizing key outstanding translational and clinical questions.