Elevated phosphorylated mammalian target of rapamycin (p-mtor) expression in human neoplasms

Abstract

10571 Background: Mammalian target of rapamycin (mTOR) regulates several cell functions critical to tumorigenesis including proliferation, growth, mobility and survival. mTOR expression and dysregulation have been reported carcinomas of breast, head & neck, liver and kidney, but have not yet been studied in non small cell lung cancers (NSCLC), colorectal adenocarcinomas (CRC), nor brain tumors including gemistocytic astrocytomas (GA) and glioblastomas (GBM). Methods: Formalin-fixed paraffin-embedded tissue sections from 121 NSCLC [45 squamous cell carcinomas (SCC), 45 pure adenocarcinomas (AC), and 31 bronchioloalveolar carcinomas (BAC) including both pure BAC and adenocarcinomas with BAC features], 108 CRC, 8 GA and 24 GBM were immunostained by an automated method (Ventana Medical Systems, Tucson, AZ) using monoclonal rabbit anti-human p-mTOR antibody (Cell Signaling, Danvers, MA). Immunohistochemical assessment included intensity and percentage of positive cells in both benign and carcinomatous elements. Results were correlated with morphologic and prognostic variables in NSCLC and CRC and GBM. Results: Elevated p-mTOR expression was noted in 33% SCCs, 64% ACs, and 65% BAC, 78% CRC, 75% GA and 96% GBM. For NSCLC, increased expression of p-mTOR correlated with histologic subtype (p=0.004). Within SCC greater than 3 cm in size, only 20% had an increase in p-mTOR, while 53% of SCC ≤ 3 cm showed an increase in p-mTOR expression (p=0.03). 100% high grade vs. 43% low grade (p=0.05) and 100% advanced stage (p=0.037) vs. 54% low stage BAC showed an increase in p-mTOR. Consistently, 100% BACs with positive lymph node status vs. 54% node negative BACs showed an increased level of p-mTOR (p=0.037). For CRC, p-mTOR over-expression correlated with high tumor grade (80% Grade 3 vs 50% Grade 1 p=0.042). Majority of GA (6/8) and nearly all GBM (23/24) were positive for p-mTOR (p=0.135). Conclusions: Activated mTOR protein, defined by phosphorylation of mTOR at Serine-2448 (p-mTOR), is increased in NSCLC, CRC and both GA and GBM. These findings suggest a potential role for mTOR dysregulation in lung, colon and brain tumorigenesis and support the currently ongoing clinical trials investigating the therapeutic relevance of rapamycin analogs in the treatment of these tumors. No significant financial relationships to disclose.