title: Targeting the ERK pathway for the treatment of Cushing's disease.
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.
authors.affiliation: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Dongyun
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Marvin
authors.initials: M
authors.lastname: Bergsneider
authors.affiliation: Department of Head and Neck Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Marilene B
authors.initials: MB
authors.lastname: Wang
authors.affiliation: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.|Department of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Heaney
mesh_terms: D049913:ACTH-Secreting Pituitary Adenoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D000236:Adenoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D057125:Nuclear Receptor Subfamily 2, Group C, Member 2 / Q000235:genetics / Q000378:metabolism; D047748:Pituitary ACTH Hypersecretion / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D014407:Tumor Cells, Cultured
chemical_list: D001562:Benzimidazoles; D057125:Nuclear Receptor Subfamily 2, Group C, Member 2; C581313:binimetinib; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone
keywords: Cushing’s disease; adrenocorticotropic hormone; proopiomelanocortin; testicular receptor 4