Epidermal growth factor receptor (EGFR) inhibitors are currently being investigated as a potential therapy for Cushing’s disease.

Various EGFR inhibitors are currently approved to treat other conditions, such as non-small cell lung cancer (NSCLC). Examples include Iressa (gefitinib) by AstraZeneca and Tarceva (erlotinib) by Astellas and Genentech.

How EGFR inhibitors work

The symptoms of Cushing’s disease are due to constant high levels of the hormone cortisol. Cortisol production and release from the adrenal gland is triggered by adrenocorticotropic hormone (ACTH). Cushing’s disease is commonly caused by a tumor in the pituitary gland that stimulates excess production of ACTH, leading to high levels of cortisol.

EGFRs are commonly overexpressed in many tumors, including pituitary tumors, and are believed to be involved in tumor growth. Furthermore, EGFRs are involved in ACTH secretion from the tumor. EGFRs stimulate the production of proopiomelanocortin (POMC), the precursor to ACTH that is essential for its production.

EGFR inhibitors work by blocking EGFRs from sending signals, which would trigger tumor growth or POMC production. It is thought that blocking EGFR in Cushing’s disease may reduce ACTH production, leading to a reduction in cortisol levels and a reduction in disease symptoms. EGFR inhibitors also aim to stop tumor growth or reduce the size of the tumor that is the cause of the condition.

EGFR inhibitors are predicted to be especially effective in Cushing’s disease patients with a mutation in the ubiquitin-specific protease 8 (USP8) gene. A mutation in this gene can cause EGFRs to be constantly active and therefore constantly signaling to produce POMC, resulting in high levels of cortisol. Two independent studies, published in the scientific journals Nature Genetics and Cell Research, demonstrated that mutations in the USP8 gene can cause increased EGFR signaling and increased cortisol levels.

EGFR inhibitors in clinical trials

A study, published in The Journal of Clinical Investigation, evaluated the effect of Iressa in pituitary tumors that have been surgically removed both in humans and in dogs. The results demonstrated that blocking EGFR with Iressa prevented POMC expression and reduced ACTH levels. However, some tumors did not express EGFR, and in these cases, Iressa was not effective.

This study also showed that in mice tumors altered to produce excess EGFR, Iressa was able to successfully reduce tumor size and decreased cortisol levels, suggesting that it could potentially be an effective treatment for Cushing’s disease.

Clinical trials in humans are required to fully assess the safety and efficacy of Iressa, and other EGFR inhibitors, in Cushing’s disease. While EGFR inhibitors are known to be safe in NSCLC, no results of Cushing’s disease specific trials have been published to date.

A group at Huashan Hospital, in China, aimed to carry out an open-label Phase 2 clinical trial (NCT02484755) testing Iressa in an estimated six Cushing’s disease patients with confirmed USP8 mutations. However, the completion date of the trial has passed and no results have been announced.

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