Among alternative therapeutic strategies in clinically aggressive
neuroendocrine tumors (NETs) of the lung, promising results have been obtained in experimental clinical trials with
mammalian target of rapamycin (
mTOR) inhibitors, though in the absence of a proven mTOR signaling activation status. This study analyzed the expression of phosphorylated mTOR (p-mTOR) and its major targets, the ribosomal p70S6-kinase (S6K) and the eukaryotic
initiation factor 4E-binding
protein 1 (4EBP1) in a large series of 218 surgically resected, malignant lung NETs, including 24 metastasizing typical
carcinoids, 73 atypical
carcinoids, 60 large cell neuroendocrine
carcinomas (LCNECs), and 61
small cell carcinomas (SCLCs). By immunohistochemistry, low-to-intermediate-grade
tumors as compared with high-grade
tumors showed higher levels of p-mTOR and phosphorylated S6K (p-S6K) (P<0.001), at variance with phosphorylated 4EBP1 (p-4EBP1), which was mainly expressed in LCNECs and SCLCs (P<0.001). The activated status of mTOR pathway was proved by the strong correlation of p-mTOR with p-S6K and
somatostatin receptor(s). Western blot analysis of NET
tumor samples confirmed such findings, and differential sensitivity to mTOR inhibition according to mTOR pathway activation characteristics was determined in two lung
carcinoid cell lines in vitro. None of the investigated molecules had an impact on survival. However, in low-grade
tumors, low p-mTOR expression correlated with
lymph node metastases (P=0.016), recurrent disease, and survival (P=0.005). In conclusion, these data demonstrate a differential mTOR activation status in the spectrum of pulmonary NETs, possibly suggesting that mTOR pathway profiling might play a predictive role in candidate patients for mTOR-targeted
therapies.