alone 0, a novel clinical quality PI3K inhibitor, alone and in combination with rapamycin. This study is the first report of the effects of NVP BKM120 in NSCLC cell lines. A recently completed phase 1 study of NVPBKM120 included two patients with pre treated lung cancer with one patient remaining on study for more than 8 months. While our AQUA data show a higher expression of p85 and p110a Flt Signaling in adenocarcinoma compared to squamous cell carcinoma, it does not appear in the limited number of cell lines that were studied that adenocarcinoma cell lines are more sensitive to PI3K inhibitors than squamous carcinoma cells. m TOR inhibitors like rapamycin and its analogues have cytostatic properties in preclinical models.
However, Dehydrogenase these drugs have had only limited activity when administered alone to patients with NSCLC, presumably because they interrupt negative feedback loops that down regulate PI3K signaling, causing paradoxical up regulation of pro survival signaling pathways. Our data suggest that rapalogs in combination with a PI3K inhibitor may limit this up regulation and could act as sensitizers to direct PI3K inhibition in NSCLC. This finding is consistent with previous reports of activity by combining PI3K and mTOR inhibitors in various types of cancer cells. Our observation that minimal mTOR inhibition is sufficient to achieve synergism with direct PI3K inhibitors is very important, as this may translate into better clinical tolerability without sacrificing efficacy of this drug combination. Dual inhibitors of PI3K and mTOR have demonstrated promising activity in a number of malignancies.
NVP BEZ235, a novel dual inhibitor of PI3K and mTOR, was highly active in all NSCLC cell lines tested with IC50s in the nanomolar range and led to downregulation of pAKT and pP70S6K. This result is consistent with the effects of NVPBEZ235 in NSCLC cell lines recently published by other investigators. In addition, we were able to demonstrate that NVP BEZ235 resulted in PARP cleavage and caspase 2 activation. This is consistent with previous studies demonstrating that NVP BEZ235 induced apoptosis through activation of caspase 2 but not caspases 8, 9 and 10. Our results with NVP BEZ235 are consistent with previous studies showing antiproliferative effects of NVP BEZ235 in a transgenic mouse model of lung cancer. NVP BEZ235 has now entered early phase clinical trials for solid tumors.
Five patients with lung cancer were included in a recently completed Phase I study with two of them demonstrating response by CT and PET criteria to NVPBEZ325. In the limited number of lung cancer cell lines that we studied the response to co inhibition by PI3K inhibitors and rapamycin or to the dual inhibitor, NVP BEZ235, was independent of wildtype or mutant EGFR status. This observation differs somewhat from a previous report by Faber et al. describing insufficient antiproliferative effects of NVP BEZ235 in the EGFR mutant NSCLC cell line HCC827. However, it has to be noted that HCC827 un