Abstract 3479: SMAC mimetic (JP1201) sensitizes non small cell lung cancers (NSCLCs) to multiple chemotherapy agents and erlotinib in an IAP dependent but TNFα independent manner

Abstract

Abstract Tumor cells have acquired resistance to apoptotic stimuli, which is thought to contribute to chemotherapy resistance. Therefore strategies to re-engage apoptotic cascades have strong therapeutic potential. One family of proteins that is key in deregulating apoptosis are the Inhibitors of Apoptosis Proteins (IAPs), which function by binding to and inhibiting caspases, and are in turn inhibited by second mitochondrial activator of caspases (SMAC). One strategy to re-sensitize tumor cells to apoptosis is to create small molecule mimetics of SMAC, such as JP1201 (Joyant Pharmaceuticals). Initial tests of JP1201 in lung cancer identified ∼15% of NSCLCs that were sensitive to low concentrations of JP1201 as a single agent. In all cases sensitive NSCLCs expressed TNFα which was required for single agent drug sensitivity (Peterson et al., 2007). To extend these findings to the large majority of NSCLCs and prepare for clinical trials, we tested 15 NSCLC lines that are resistant to single agent JP1201 (IC50 ≥ 100 µM) in combination with cisplatin, doxorubicin, gemcitabine, erlotinib, paclitaxel, and vinorelbine in a 5 day MTS based microtiter assay. We find great heterogeneity among NSCLCs in tumor cell response phenotypes to combined JP1201 + chemotherapy agents and that for each NSCLC at least one chemotherapy was sensitized by JP1201 100 to 10,000 fold (significant combination indices). Of note we found no NSCLC where cisplatin was sensitized by JP1201. Surprisingly, we also found examples of antagonism when JP1201 is added. Using siRNAs targeted to cIAP1, cIAP2, and XIAP we found that for gemcitabine, XIAP is the key IAP whose inhibition by JP1201 leads to sensitization, while for paclitaxel and vinorelbine, knockdown of any of the three IAPs sensitizes NSCLCs. None of the treatments induce secretion of TNFα or TRAIL (detected by ELISA) in this panel of NSCLCs. NOD/SCID mice bearing NSCLC NCI-H1395 xenografts were randomized (8 mice per group) to 3 weeks of treatment with saline, 25 mg/kg gemcitabine, 2.4 mg/kg vinorelbine, 6 mg/kg JP1201, gemcitabine + JP1201, and vinorelbine + JP1201. Tumor burden was reduced 60% in mice treated with gemcitabine + JP1201 compared to gemcitabine alone, and 70% in mice treated with vinorelbine + JP1201 compared to vinorelbine alone. We conclude that preclinical studies show the combination of JP1201 with chemotherapy is a valid therapeutic strategy for 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 3479.