The New Molecular Landscape of Cushing's Disease

Cushing's disease (CD) is caused by corticotropin-secreting pituitary adenomas and results in substantial morbidity and mortality. Its molecular basis has remained poorly understood until the past few years, when several proteins and genes [such as testicular orphan nuclear receptor 4 (TR4) and heat shock protein 90 (HSP90)] were found to play key roles in the disease. Most recently, mutations in the gene of ubiquitin-specific peptidase 8 (USP8) increasing its deubiquination activity were discovered in a high percentage of corticotroph adenomas. Here, we will discuss emerging insights in the molecular alterations that finally result in CD. The therapeutic potential of these findings needs to be carefully evaluated in the near future, hopefully resulting in new treatment options for this devastating disorder.

TrendsTranssphenoidal surgery and radiotherapy are the treatment of choice in CD. However, despite high initial remission rates, a significant percentage of patients relapse.Owing to the poor understanding of the pathophysiology of CD, drug therapy is still limited and often only ameliorates the clinical manifestations through blocking of ACTH release or adrenal cortisol synthesis.Recent research has identified several important proteins (e.g., EGFR, HSP90, TR4, and AVPR1b) whose deregulation is associated with CD and may therefore represent potential therapeutic targets.Frequent, novel mutations in the USP8 gene that are associated with corticotroph pituitary adenomas were recently discovered that result in reduced EGFR degradation and increased POMC activation in vitro.