title: Mammalian target of rapamycin signaling activation patterns in neuroendocrine tumors of the lung.
abstract: 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.
authors.affiliation: Division of Pathology, Department of Clinical and Biological Sciences, University of Turin at San Luigi Hospital, Regione Gonzole 10, Orbassano, Turin, Italy. luisella.righi@unito.it
authors.forename: Luisella
authors.initials: L
authors.lastname: Righi
authors.forename: Marco
authors.initials: M
authors.lastname: Volante
authors.forename: Ida
authors.initials: I
authors.lastname: Rapa
authors.forename: Veronica
authors.initials: V
authors.lastname: Tavaglione
authors.forename: Frediano
authors.initials: F
authors.lastname: Inzani
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pelosi
authors.forename: Mauro
authors.initials: M
authors.lastname: Papotti
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D010766:Phosphorylation; D011379:Prognosis; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus