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, psychologic distress, iatrogenic morbidity, and pathology associated with an advanced, invasive disease. Many tumors exploit glucocorticoid signaling to provide antiapoptotic 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 nonclinical data show that selective GR antagonists (SGRA) synergize with anticancer agents, including taxanes, androgen receptor inhibitors, PARP inhibitors, and anti-programmed cell death ligand 1 (PDL-1) immune checkpoint inhibitors, driving improved anticancer activity. In a tumor-intrinsic manner, SGRAs downregulate the antiapoptotic 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 antiandrogen therapy mediated through the GR and have the potential for additive anticancer 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.