Breast Cancer Treatment Lapatinib May Have Role as Cushing’s Syndrome Therapy, Pre-clinical Study Shows

Blocking the EGFR signaling pathway using the breast cancer treatment lapatinib significantly reduces the amount of adrenocorticotropic hormone (ACTH) produced by pituitary tumor cells and their proliferation in mice, a preclinical study shows.

The findings suggest lapatinib — marketed as Tykerb by Novartis in the United States — and other blockers of the EGFR signaling are promising treatments for patients with Cushing’s disease.

The study supporting this research, “Lapatinib decreases the ACTH production and proliferation of corticotroph tumor cells,” was published in the Endocrine Journal.

Cushing’s syndrome, a condition caused by a pituitary tumor producing too much ACTH, leads to several metabolic problems in patients, including osteoporosis, infections, high blood sugar, high blood pressure, and atherosclerosis.

The condition is normally treated with surgery, but some patients require additional therapies that control ACTH and cortisol excess.

Investigators have found that most ACTH-producing pituitary tumors carry mutations in the USP8 gene. These mutations prevent the epidermal growth factor receptor (EGFR) from being degraded and lead to a constantly active signaling pathway.

Because EGFR (epidermal growth factor receptor) is involved in many functions, one of them being a stimulatory role for the synthesis of ACTH, researchers hypothesized that inhibiting this signaling pathway could help treat ACTH-expressing pituitary tumors.

Japanese investigators studied the effects of lapatinib in pituitary tumor cells, as well as in animal models implanted with these same cells.

Lapatinib, already approved for the treatment of breast cancer patients, is an agent that inhibits both the EGFR and the HER2 proteins. Its well-established safety profile and broad anti-tumor activity, including in HER2-positive pituitary tumors, makes it an attractive compound for additional studies.

Researchers found that lapatinib-treated cells had a reduction in the amount of EGFR they produced. As a result, they produced much less ACTH and expressed fewer genes involved in tumor growth, which reduced cell proliferation and induced the death of these cells.

When tested in mice implanted with the ACTH-producing tumor cells, lapatinib behaved in a similar manner, significantly reducing tumor size and lowering ACTH and cortisol levels, compared to untreated mice.

“Inhibition of EGFR signaling contributes to inhibition of ACTH production and cell proliferation in [ACTH-producing] tumor cells. Therefore, an EGFR-targeting therapy might be clinically important in Cushing’s disease,” researchers concluded.