was also the cell line least sensitive to NVP BEZ235 in our hands. We explored the possibility of targeting the PI3K AKT pathway at multiple levels by adding the direct EGFR tyrosine kinase inhibitor erlotinib to the dual inhibition of PI3K and mTOR by NVP BEZ235. Erlotinib is approved by the FDA as single agent therapy for NSCLC after first flt-3 inhibitors in clinical trials and second line chemotherapy, however the response rates are low at an average of 8.9 and the median duration of response is modest at 7.9 months. While we observed a wide range of IC50s for erlotinib which spanned four logs between the most sensitive and the most resistant cell lines, erlotinib potentiated the growth inhibition by NVP BEZ235 in all cell lines studied.
These results support a potential therapeutic role of co targeting of EGFR and the PI3K pathway and suggest that this approach should be evaluated further for patients with NSCLC. Of note, the concentrations of erlotinib used in majority of these experiments were ICG-001 well below the reported steady state level of erlotinib achieved in actual patients. In summary, here we showed that PI3K expression is associated with advanced stage and decreased survival in NSCLC, suggesting that it might be a good drug target for this disease. The p110a subunit was strongly co expressed with mTOR. Concurrent inhibition of PI3K and mTOR was synergistic in all NSCLC cell lines studied and resulted in growth inhibition and apoptosis. It appeared that minimal amount of rapamycin in the nanomolar range was sufficient to potentiate the effect of the PI3K inhibitors, LY294002 and NVP BKM 120.
This could potentially translate into decreased toxicity and better clinical tolerability of the drug combination. Dual inhibition of PI3K and mTOR by NVP BEZ 235 is promising and should be further evaluated in clinical trials for patients with NSCLC alone and in combination with EGFR inhibitors. It has been more than 20 years since phosphatidylinositol 3 kinase was first discovered. The transforming ability of viral oncoproteins relied on an association with a PI3K lipid kinase activity.1 4 Over the ensuing years, studies established the central role of PI3K signaling in several cellular processes critical for cancer progression, including metabolism, growth, survival, and motility. Inappropriate co option of PI3K signaling is one of the most frequent occurrences in human cancer.
5,6 Consequently, significant efforts have been made to generate inhibitors of the PI3K pathway to treat cancers. However, it remains unknown which cancers will benefit most from these treatments and how to best use such therapeutics. In addition, the many possible untoward biologic sequelae of PI3K inhibition may limit the potential therapeutic gain of PI3K pathway inhibition. Here we will review data demonstrating the role of PI3K in tumor development and maintenance. We will compare the different potential therapeutic options for inhibiting this pathway and ho