Priority Research Papers:

Targeting the ERK pathway for the treatment of Cushing’s disease

Dongyun Zhang, Marvin Bergsneider, Marilene B. Wang and Anthony P. Heaney _

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Oncotarget. 2016; 7:69149-69158. https://doi.org/10.18632/oncotarget.12381

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Dongyun Zhang1, Marvin Bergsneider2, Marilene B. Wang3 and Anthony P. Heaney1,2

1 Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

2 Department of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

3 Department of Head and Neck Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

Correspondence to:

Anthony P. Heaney, email:

Keywords: adrenocorticotropic hormone, Cushing’s disease, proopiomelanocortin, testicular receptor 4

Received: July 25, 2016 Accepted: September 22, 2016 Published: September 30, 2016


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.

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