Epidermal growth factor receptor (EGFR) inhibitors are being considered as a potential therapy for Cushing’s disease, although clinical studies into their use are quite limited to date.

The U.S. Food and Drug Administration (FDA) has approved various EGFR inhibitors to treat other conditions, such as non-small cell lung cancer (NSCLC). Examples of these treatment for NSCLC include Iressa (gefitinib) by AstraZeneca, and Tarceva (erlotinib) by Astellas and Genentech.

How do EGFR inhibitors work?

The symptoms of Cushing’s disease develop as a result of constantly high levels of the hormone cortisol. The adrenocorticotropic hormone (ACTH) triggers the production and release of cortisol from the adrenal glands. Cushing’s disease is the result of a tumor in the pituitary gland that stimulates excess production of ACTH, leading to excessive cortisol levels.

Many tumors, including pituitary tumors, commonly express high levels of EGFRs. Researchers think that EGFRs also play a role in tumor growth. Furthermore, EGFRs trigger the secretion of ACTH from the tumor by stimulating the production of proopiomelanocortin (POMC). This is the precursor to ACTH that is essential for its production.

EGFR inhibitors work by blocking EGFRs from sending signals that would trigger tumor growth or POMC production. Researchers think that blocking EGFR in Cushing’s patients, for this reason, may lower ACTH production. This would likely lead to a reduction in cortisol levels and an easing of disease symptoms. EGFR inhibitors also aim to stop tumor growth and reduce in size the tumor that is the cause of the condition.

Researchers expect EGFR inhibitors to be especially effective in Cushing’s patients with a mutation in the USP8 gene.  Mutations in this gene can cause EGFRs to be constantly active, meaning they are constantly signaling to produce POMC, which can result in high levels of cortisol. Two independent studies, published in the scientific journals Nature Genetics and Cell Research, demonstrated that USP8 mutations did exactly that: increased EGFR signaling that prompted high cortisol levels.

EGFR inhibitors in clinical trials for Cushing’s

A study, published in The Journal of Clinical Investigation, evaluated what effects use of Iressa had on pituitary tumors that researchers surgically removed from both people and dogs. Results demonstrated that blocking EGFR with Iressa prevented POMC expression, and reduced ACTH levels. When tumors did not express EGFR, as was the case for some, Iressa was not effective. This study also showed that in mouse tumors altered to produce EGFR in excess, Iressa was able to successfully lessen tumor size and lower cortisol levels. These results suggest that Iressa could potentially be an effective treatment for Cushing’s disease.

Researchers at Huashan Hospital, in China, initiated an open-label Phase 2 clinical trial (NCT02484755) testing Iressa in six Cushing’s disease patients with confirmed USP8 mutations. However, this trial was due to end in September 2015, and no results have been announced.  Whether it took place or was ended early is not known.

Clinical trials in Cushing’s patients are essential to fully assess the safety and efficacy of Iressa or other EGFR inhibitors as a disease treatment. While researchers know EGFR inhibitors to be safe in those with NSCLC, no results of Cushing’s disease-specific trials have been published to date.

 

Last updated: April 27, 2020

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