Expression of mTORC1/2-related proteins in primary and brain metastatic lung adenocarcinoma

Abstract

Brain metastases are common complications of adenocarcinomas of the lung and are associated with a poor prognosis. Although an increasing amount of data indicates that dysregulated activity of mammalian target of rapamycin (mTOR) can influence the metastatic potential of various tumors, the role of mTOR complexes in the development of brain metastases from adenocarcinomas of the lung is largely unknown. To estimate mTOR activity, we studied the expression of mTOR related proteins (mTORC1: p-mTOR, p-S6; mTORC2: p-mTOR, Rictor) in primary (n=67) and brain metastatic (n=67) lung adenocarcinomas, including 15 paired tissue samples, using immunohistochemistry and tissue microarrays. Correlation with clinicopathological parameters was also analyzed. Increased p-mTOR, p-S6 and Rictor expressions were observed in 34%, 33% and 37% of primary adenocarcinomas and in 79%, 70% and 66% of brain metastases, respectively. Expression of these markers was significantly higher in brain metastases as compared to primary carcinomas (P<.0001, P<.0001, P<.001). Rictor expression was significantly higher in primary ADCs of the paired cases with brain metastases as compared to primary ADCs without brain metastases (67% vs. 28%, P<.01). No other statistically significant correlations were found between mTOR activity and clinicopathological parameters. The increased mTORC1/C2 activity in a subset of pulmonary adenocarcinomas and the higher incidence of increased mTORC1/C2 activity in brain metastases suggest that the IHC panel for characterizing mTOR activity and its potential predictive and prognostic role warrants further investigations.