An important cellular pathway involved in multiple cancers could potentially be targeted to treat adrenal cancers that cause Cushing’s syndrome, a study has found.
The study, “MAPK/ERK pathway inhibition is a promising treatment target for adrenocortical tumors,” was published in the Journal of Cellular Biochemistry.
In about 30% of cases, Cushing’s syndrome is caused by the excessive release of cortisol by a tumor in one of the adrenal glands, the organs where several important steroid hormones are produced, including cortisol.
In some patients, this tumor may become malignant and affect the outer layer (or cortex) of the adrenal gland, known as an adrenocortical carcinoma (ACC). This type of cancer is very rare, and the molecular mechanisms behind its development are largely unknown.
To gain insight on these mechanisms, a team led by researchers at Instituto de Investigação e Inovação em Saúde and Hospital São João, both in Porto, Portugal, set out to investigate the role of an important pathway cells use to communicate signals in response to a variety of internal and external cues — the MAPK-MEK-ERK pathway.
It is well-known that several elements of this pathway are altered in cancer, and some of its players are being investigated as promising anti‐tumor targets.
“Thus, exploring the consequences of these pathway’s alterations in ACC is needed to identify more effective treatments that can target these cancers’ multiple features,” the researchers said.
To study the role of the MAPK‐MEK‐ERK pathway in tumor progression, they specifically looked at the activation of three proteins belonging to this pathway — ERK1, ERK2 and p38 — in normal and tumoral adrenal gland tissue samples.
They used adrenal gland samples from 10 patients with incidentalomas (benign or malignant adrenal tumors discovered by chance on imaging exams), 12 with benign Cushing’s syndrome, six with malignant Cushing’s syndrome (adrenocortical carcinoma), and eight with normal adrenal glands.
Activation of ERK1 and ERK2 proteins was significantly higher in the adrenal glands of patients with malignant Cushing’s syndrome than in all other groups, including those with benign tumors.
In contrast, the activated form of p38 was absent from malignant Cushing’s syndrome samples, despite being present in the other groups, which suggested that it is the activation of ERK proteins that plays an important role in cancer cell formation and growth.
Based on these observations, researchers then tested to see if inhibiting the ERK1 and ERK2 proteins could be a potential therapeutic strategy for adrenocortical carcinoma.
They demonstrated that a compound called PD184352 that specifically inhibits the activation of ERK1 and ERK2 was able to reduce the proliferation, survival, and production of cortisol in a cell line of adrenocortical carcinoma growing in the lab.
Complete surgical removal is the only available treatment able to cure adrenocortical carcinoma. However, the cancer still comes back in many of the patients who have this surgery.
“Thus, there is an unquestionable need to identify alternative drug targets to improve ACC treatment and prognosis,” the researchers said.
“This data suggests that MEK‐MAPK‐ERK signaling has a role in adrenocortical tumorigenesis that could be potentially used as a diagnostic marker for malignancy and targeted treatment in ACC,” they concluded.
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