Editors' ChoiceEndocrinology

Cushing’s Disease Escapes the Knife

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Science Translational Medicine  14 Dec 2011:
Vol. 3, Issue 113, pp. 113ec201
DOI: 10.1126/scitranslmed.3003553

Nowadays, many people blame their hormones for making them fat. For patients with Cushing’s disease, hormones do make them fat—and diabetic, hypertensive, and osteoporotic. Cushing’s disease is a rare disorder of excess cortisol production driven by adrenocorticotrophic hormone (ACTH)–secreting pituitary tumors. Surgical removal of the tumor is the mainstay of therapy in this disease, but remission rates may be limited, depending on the size of the tumor or the experience of the surgeon. No drugs are available to target these pituitary tumors, and current medical therapies that block cortisol production are limited. Fukuoka and colleagues now provide new hope for medical therapy in Cushing’s disease by using a drug already vetted in oncology.

Because 60% of ACTH-secreting tumors express the epidermal growth factor receptor (EGFR), the authors hypothesized that EGFR could be an important tumor regulator and therapeutic target in Cushing’s disease. To study the role of EGFR signaling in corticotroph (ACTH-secreting) tumors, they took advantage of a known inhibitor of EGFR, gefitinib. Gefitinib is a tyrosine kinase inhibitor that has been used successfully to treat lung adenocarcinomas and other tumors that overexpress EGFR. Strikingly, in primary cell cultures of resected human corticotroph tumors, the addition of gefitinib produced a dose-dependent reduction in the expression of propriomelanocortin (POMC), the precursor protein of ACTH. Using a mouse corticotroph tumor line, Fukuoka et al. went on to demonstrate that signaling through EGFR enhances POMC expression and ACTH secretion through activation of the mitogen-activated protein kinase pathway; addition of gefitinib suppresses this activity and also led to increased apoptosis of the tumor cells. Most importantly, gefitinib treatment of mice grafted with EGFR+ corticotroph tumors led to a reduction in tumor size and ameliorated the effects of excess cortisol production, with improvement in body weight, omental (abdominal) fat, blood glucose, and corticosterone levels.

Though not all ACTH-secreting tumors will be EGFR+ and respond to gefitinib, the work of Fukuoka and colleagues has introduced a potential new therapy for Cushing’s disease. Future clinical trials will be critical to evaluating the efficacy of gefitinib in the medical treatment of this disorder.

H. Fukuoka et al., EGFR as a therapeutic target for human, canine, and mouse ACTH-secreting pituitary adenomas. J. Clin. Invest. 121, 4712–4721 (2011). [PubMed]

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