The aberrant activation of Hedgehog/Gli transcriptional factor has been implicated with a broad spectrum of lethal tumors. Targeted inhibition at cell membrane level of the Hh pathway, i.e. Smo and Hh inhibitors, has shown promising anti-tumor activity in both preclinical and clinical trials. A growing body of evidence has revealed additional mechanisms of Gli activation which are independent of Hh/SMO regulation and are stimulated by the crosstalk between components downstream of Hh/Smo and several other oncogenic signaling pathways, such as the Epidermal Growth Factor Receptor (EGFR) pathways. We hypothesized that the simultaneous inhibition of the EGFR pathway and Gli function could abrogate the interaction and result in synergistic anti-tumor effects. In order to test this hypothesis, we have undertaken studies in multiple lung cancer and mesothelioma cell lines. Effects of combination treatments with EGFR tyrosine kinase inhibitor erlotinib and an Hh pathway inhibitor were examined by using MTS assay. In our studies, the application of the Hh pathway inhibitor sensitized lung cancer cells to erlotinib treatment with a higher than 10 fold decrease of IC50. We also used the CalcuSyn software to calculate Combination Index (CI), in order to evaluate the effects of combination treatments (CI<1 indicates Synergism, CI=1 indicates Additive effects, and CI>1 indicates Antagonisim). In many lung and mesothelioma cell lines, the dual treatment of the Hh inhibitor and erlotinib showed synergistic effects with a Combination Index (CI) lower than 0.7. To elucidate the mechanism of the crosstalk between the two pathways, we have examined the activities of EGFR and Hh pathways upon single and dual treatments. Based on our studies, we speculate that dual inhibition of Hh/Gli and EGFR pathways may become a promising targeted therapy for lung cancers and mesothelioma.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B212.