51. Targeting the ERK pathway for the treatment of Cushing’s disease
- Author
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Zhang, Dongyun, Bergsneider, Marvin, Wang, Marilene B, and Heaney, Anthony P
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,2.1 Biological and endogenous factors ,Aetiology ,ACTH-Secreting Pituitary Adenoma ,Adenoma ,Adrenocorticotropic Hormone ,Animals ,Benzimidazoles ,Cell Line ,Tumor ,Cell Proliferation ,Gene Expression ,Humans ,MAP Kinase Signaling System ,Mice ,Nuclear Receptor Subfamily 2 ,Group C ,Member 2 ,Pituitary ACTH Hypersecretion ,Pro-Opiomelanocortin ,Promoter Regions ,Genetic ,Protein Binding ,Tumor Cells ,Cultured ,adrenocorticotropic hormone ,Cushing's disease ,proopiomelanocortin ,testicular receptor 4 ,Cushing’s disease ,Oncology and carcinogenesis - Abstract
We recently demonstrated that the orphan nuclear receptor testicular receptor 4 (TR4) is a potent regulator of corticotroph tumor growth and hormone secretion. The Ras/Raf/MEK/ERK pathway is commonly overactivated in human tumors and we have demonstrated that corticotroph tumor TR4 is activated by ERK1/2-mediated phosphorylation. We evaluated effects of MEK-162, a selective, non-ATP-competitive allosteric inhibitor of MEK1/2, on murine and human in vitro and in vivo corticotroph tumor proliferation and adrenocorticotrophic hormone (ACTH) secretion. MEK-162 treatment dose-dependently inhibited corticotroph tumor proliferation, induced apoptosis, reduced pro-opiomelanocortin (POMC) mRNA levels and inhibited ACTH secretion in vitro. Similar findings were obtained in human corticotroph tumor primary cultures (n = 5). These actions of MEK-162 were augmented in the presence of TR4 overexpression, suggesting that TR4 levels may serve as a predictive biomarker of MEK-162 corticotroph tumor responsiveness. Additionally, MEK-162 treatment reduced TR4 protein expression and blocked recruitment of TR4 to bind its consensus site on the POMC promoter (-854bp to -637bp), elucidating multiple mechanisms to control TR4 corticotroph tumor actions. In a murine corticotroph tumor in vivo model of Cushing's disease, MEK-162 treatment inhibited tumor growth and reduced tumor-derived circulating plasma ACTH, and corticosterone levels. These results demonstrate the potent actions of MEK-162 to inhibit corticotroph tumor growth and hormone secretion in vitro and in vivo via TR4-dependent and independent mechanisms, and raise the possibility of MEK-162 as a novel therapy for Cushing's disease.
- Published
- 2016