Proteins Marker Could Identify Aggressive Lung Cancers

A specific pair of proteins more often found in aggressive smoking-related lung cancer could serve as a prognostic biomarker for aggressive disease. The protein ASCL1 and increased expression of the RET oncogene could represent a potential aggressive subtype of lung adenocarcinoma, according to a study published in the journal Oncogene.

The targets may also be “druggable,” said George Vasmatzis, PhD, an assistant professor of laboratory medicine and pathology at the Mayo Clinic in Rochester, Minnesota, and senior author of the study. RET has been previously linked to small-cell lung cancer and thyroid cancer.

The research shows that patients with tumors with high levels of the RET protein did not survive as long as ASCL1 patients with low levels of RET.

Out of a sample set of 367 stage I lung adenocarcinomas, a consistently higher level of RET expression was found in those tumors that had high ASCL1 expression compared with those that had low ASCL1 expression. Linking the expression to clinical outcomes, Vasmatzis found that high levels of RET expression in ASCL1-positive tumors correlated with shorter survival for the stage I lung cancer patients (P = .007) and in all adenocarcinoma samples (P = .037).

“RET expression in the tumors was only significant when ASCL1 expression was also present,” said Vasmatzis. “Without expression of ASCL1, the amount of RET protein present did not correlate with survival.”

Staining for neuroendocrine differentiation has previously been used to assess the aggressiveness of lung adenocarcinomas, but which markers are appropriate and whether neuroendocrine differentiation in non–small-cell lung cancer is significant remains debatable. Some studies suggest that neuroendocrine differentiation correlates with poor prognosis and a poor response to chemotherapy, while other studies show no difference in outcomes or response to therapies, according to the authors.

“Our study provides evidence that [neuroendocrine differentiation] in adenocarcinoma is triggered by smoking. [We also show that neuroendocrine differentiation] can be characterized by ASCL1 overexpression, and can progress to a more aggressive disease by overexpressing the RET protein,” said lead author Farhad Kosari, PhD, of the department of molecular medicine, at the Mayo Clinic, in Rochester, Minnesota.

ASCL1 is known to control neuroendocrine cell development and was previously linked to regulation of thyroid and small-cell lung cancer development but not smoking-related lung cancer. The gene has a specific lung differentiation role and mouse studies show it may help promote lung tumorigenesis.

A lung tumor sample analysis of 115 tumors in the current study found that neuroendocrine differentiation is rare in adenocarcinomas from patients with no history of smoking, suggesting that this differentiation is linked to smoking-related lung cancer.

Using a lung adenocarcinoma cell line with high ASCL1 and RET levels, the authors showed that decreasing levels of ASCL1 protein resulted in slower-growing cells and a decrease in motility.

Whether ASCL1 directly regulates RET is not clear and whether other signals may influence RET expression and activity, although ASCL1 acts upstream of RET.

Further studies are needed to understand whether ASCL1-positive, high RET expression lung tumors are a distinct subset of lung tumors and whether this potential biomarker pair could be exploited as a target for new therapies.

The researchers are currently developing a better immunohistochemistry staining assay to detect the levels of both proteins. Vasmatzis and colleagues are also testing the effectiveness of RET inhibitors on ASCL1 and RET overexpressing cell lines.