Mammalian target of rapamycin (mTOR) is a key kinase downstream of PI3K/AKT predominantly involved in translational control. Despite the well known role of mTOR in carcinogenesis, its prognostic potential in lung cancer has not been investigated. mTOR is an attractive target for biological therapies however results of early clinical trials have been disappointing in non small cell lung cancer (NSCLC). It is possible that this is a result of treatment of patients that are not selected for mTOR pathway activation since there is no companion diagnostic test that identifies mTOR dependent tumors.Here, we quantitatively assessed mTOR protein expression in NSCLC patients in two large data sets to investigate its impact on survival and we subsequently studied mTOR signaling in a series of NSCLC cell lines with different responses to mTOR inhibition to identify surrogate markers for sensitivity to mTOR targeted therapies. Automated quantitative analysis (AQUA®), a fluorescent-based method for analysis of in situ protein expression, was used to assess mTOR expression in a training cohort of 167 NSCLC patients. An independent validation cohort of 235 NSCLC patients was used to validate mTOR classification and evaluate outcome. Tumors expressed mTOR in the cytoplasm in 65% and 58% of the cases in training and validation sets respectively; mTOR expression was not associated with clinical or pathological characteristics. Survival analysis showed that patients with high mTOR expression had a longer median overall survival compared to the low expressers (51.1 vs 38.5 months, log rank p=0.02) which was more prominent in the adenocarcinoma (AC) group (55.1 vs 39.3 months, log rank p=0.009). Multivariate analysis revealed an independent lower risk of death for AC and AC stage I patients with mTOR expressing tumors (HR=0.49, 95% CI 0.24-1.04, p=0.05 and HR=0.46, 95% CI 0.22-0.96, p=0.039 respectively). We hypothesized that those patients may favor from mTOR inhibition and/or mTOR could be a surrogate marker for sensitivity to mTOR targeted therapies and tested this hypothesis on a series NSCLC cell lines (HCC193, H1355, HCC2279, H1666, H2882, H441, H1650 and H1299). AQUA revealed a range of mTOR expression and our findings were confirmed by western blotting (WB). Cells were subsequently treated with rapamycin; interestingly dose-response curves revealed that high mTOR expressing H1299 AC cells were significantly more sensitive to rapamycin compared to low mTOR expressing HCC193 AC cells. Furthermore, WB analysis showed distinct expression and phosphorylation patterns of mTOR downstream effectors (p70 S6K, 4EPB-1 and S6) among cell lines with different sensitivity to rapamycin. mTOR expression defines a subgroup of patients with a favorable outcome and may be useful for prognostic stratification of NSCLC patients as well as incorporation of mTOR protein expression into clinical decisions.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3842.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

American Association for Cancer Research
2009