Standard chemotherapy for non-small cell lung cancer often uses doublet combinations of cisplatin or carboplatin with gemcitabine, paclitaxel, docetaxel, vinorelbine, or etoposide. While clinical responses and survival benefits are seen these are very modest and new more effective therapies are needed. As one approach to this problem we recently developed a small molecule mimetic of SMAC, a mitochondrial protein that inhibits the inhibitors of apoptosis proteins (IAPs) as a potential new chemotherapy agent (Li L, et. al. Science. (2004) 305: 1471-1474). Here we explore SMAC mimetic as a potential therapy for NSCLC, as well as the benefits of using it in conjunction with traditional chemotherapies. We tested 50 non-small cell lung cancer lines (NSCLCs) for their in vitro sensitivity to the SMAC mimetic or combined with other chemotherapy agents in a 96 hour MTS assay. Most NSCLC lung cancer lines were completely resistant to treatment with the SMAC mimetic alone (IC50 >>10μM). However, 10/50 NSCLC lines were killed by the SMAC mimetic alone at IC50s <10μM. We then tested 10 SMAC mimetic resistant NSCLCs using a co treatment with 10μM SMAC mimetic (a dose that had no effect) and various concentrations of doxorubicin, gemcitabine, paclitaxel, or vinorelbine to determine the IC50 compared with treatment of the drugs without the SMAC mimetic. We found that the NSCLC lines varied widely in their response to combined treatment but that each of them showed increases of drug sensitivity of 30 to 30,000 fold to at least some drug combination. Similarly, the drugs combined with the SMAC mimetic showed different patterns across the cell line panel and that the data are consistent with the SMAC mimetic greatly synergizing the effect of conventional chemotherapy agents. We conclude that SMAC mimetic is a promising adjuvant to conventional chemotherapies, used in the treatment of NSCLCs in what appears to be great synergy of anti tumor effects. In addition, NSCLCs show great variation in their response to various SMAC mimetic chemotherapy combinations indicating the need for personalized selection of therapy for individual tumors.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA