Disease- and treatment-associated acquired glucocorticoid resistance

The development of resistance to glucocorticoids (GCs) in therapeutic regimens poses a major threat. Generally, GC resistance is congenital or acquired over time as a result of disease progression, prolonged GC treatment or, in some cases, both. Essentially, disruptions in the function and/or pool of the glucocorticoid receptor alpha (GR alpha) underlie this resistance. Many studies have detailed how alterations in GR alpha function lead to diminished GC sensitivity; however, the current review highlights the wealth of data concerning reductions in the GR alpha pool, mediated by disease-associated and treatment-associated effects, which contribute to a significant decrease in GC sensitivity. Additionally, the current understanding of the molecular mechanisms involved in driving reductions in the GR alpha pool is discussed. After highlighting the importance of maintaining the level of the GR alpha pool to combat GC resistance, we present current strategies and argue that future strategies to prevent GC resistance should involve biased ligands with a predisposition for reduced GR dimerization, a strategy originally proposed as the SEMOGRAM-SEDIGRAM concept to reduce the side-effect profile of GCs.