Abstract 1787: Dual targeting of PI3K and mTOR results in synergistic growth inhibition in NSCLC cells

Abstract

Abstract Background: Alterations of components in the PI3K/mTOR pathway can result in malignant transformation and are found in a multitude of human cancers including non-small cell lung cancer (NSCLC). Our purpose was to characterize expression of p85 and p110α PI3K subunits in NSCLC specimens and assess the association with mTOR expression, and to study the effects of co-inhibiting PI3K and mTOR in NSCLC cell lines. Methods: Using Automated Quantitative Analysis (AQUA), a novel method of in situ protein measurement, we quantified expression of PI3K subunits in two cohorts of 251 and 192 resected NSCLC specimens. AQUA scores were correlated with clinical and pathological variables and previously published AQUA scores for mTOR. We studied changes in viability of 6 NSCLC cell lines exposed to two PI3K inhibitors, LY294002 and NVP-BKM-120, alone and in combination with rapamycin, and assessed the activity of a dual PI3K/mTOR inhibitor, NVP-BEZ-235, which is in clinical development. Results: p85 and p110α tend to be co-expressed (p<0.001), and higher expression of p85 was seen in adenocarcinomas than squamous cell carcinomas (SCC). High expression of p85 correlated with poor survival (p< 0.0075). Expression of p110α correlated with mTOR (ρ=0.30). In 6 NSCLC cell lines (3 adenocarcinomas, 3 SCC) the addition of rapamycin to LY294002 or NVP-BKM-120 was highly synergistic. Of note, even small concentrations of rapamycin (1ηM) resulted in sensitization to the PI3K inhibitors, and similar reduction in viability was seen with the addition of 1ηM, 100ηM and 1000ηM of rapamycin. NVP-BEZ-235 was highly active in NSCLC cell lines with IC50s in the ηM range and resultant down-regulation of pAkt and pP70S6K. Conclusions: PI3K is associated with decreased survival in NSCLC, suggesting that it is a good drug target for this disease. Concurrent inhibition of PI3K and mTOR is synergistic in NSCLC cell lines. Dual inhibition of PI3K and mTOR by NVP-BEZ-235 is promising and should be further evaluated in clinical trials for patients with NSCLC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1787.