A new medical therapy for Cushing disease?

Abstract

Members of the ErbB family of cell surface tyrosine kinase receptors are important targets for cancer treatment because they frequently contribute to the pathogenesis of malignancy. In this issue of the JCI, Fukuoka et al. generate data that suggest that using a tyrosine kinase inhibitor (TKI) against epidermal growth factor receptor (EGFR; also known as ErbB1) may be a novel approach for treating patients with hypercortisolemia due to pituitary corticotroph adenomas (Cushing disease). While surgical resection remains the cornerstone of treatment for individuals with such tumors, this study suggests that TKIs could perhaps be used to reduce tumor size prior to surgery or to treat recurrent disease after surgery.

Figure 1. The hypothalamic-pituitary-adrenal (HPA) axis in healthy controls and patients with Cushing disease.

The normal HPA axis is subject to negative feedback regulation by circulating cortisol levels. Cortisol normally regulates carbohydrate, protein, and lipid metabolism and plays a key role in the immune system. In Cushing disease, a pituitary corticotroph adenoma secreting too much ACTH activates the HPA axis, resulting in defective negative feedback and excessive cortisol production. Patients exhibit central obesity, hypertension, hyperglycemia, osteoporosis, and muscle atrophy.

Figure 2. Proposed function of the EGFR in pituitary corticotrophs.

(A) Relationship between Pomc expression (which encodes a precursor protein that can be cleaved to generate ACTH) and pituitary cell growth mediated by the MAPK pathway. Corticotroph adenomas have aberrant MAPK pathway activation, resulting in pituitary cell growth and increased Pomc expression (4). (B) Use of a TKI reduces corticotroph adenoma growth and Pomc expression, which is mediated by the MAPK signaling pathway.