Synergistic Effect Of A Hedgehog Pathway Inhibitor In Combination With Erlotinib On Multiple Carcinoma Cell Lines

The aberrant activation of Hedgehog(Hh)/Gli signaling has been implicated in a broad spectrum of malignant tumors. Targeted inhibition at the cell membrane of Hh pathway, for example with Smoothened(Smo) and Hh inhibitors, has shown promising preclinical and clinical anti-cancer activity. However, a growing body of evidence has revealed additional mechanisms in the activation of the Gli pathway that are independent of Hh/Smo regulation. These mechanisms are stimulated by the cross-talk between downstream components of the Hh/Smo and other oncogenic signaling pathways, such as the Epidermal Growth Factor Receptor (EGFR) pathway. Based on this, we hypothesized that the simultaneous inhibition of the EGFR pathway and Gli pathway would result in synergistic anti-tumor effects. To test this hypothesis, we used erlotinib, an EGFR tyrosine kinase inhibitor (TKI), in combination an Hh pathway inhibitor on various lung and mesothelioma cancer cell lines. It has been demonstrated that erlotinib and other TKIs are active in lung cancers with EGFR gene mutations, while not as effective in those with wild type EGFR. However in our studies, the application of the Hh pathway inhibitor sensitized EGFR wild type cells to erlotinib treatment with more than a 10-fold decrease of IC50 in multiple lung cell lines. In addition, the dual treatment resulted in promising synergism in both mesothelioma and lung cancer cell lines with a combination index of less than 0.7. To study the mechanism of crosstalk between the two pathways, we have examined the activities of EGFR, Hh and Wnt pathways in single and dual treatments. Based on our results, we believe that dual inhibition of Hh/Gli and EGFR pathways may be a promising targeted therapy for lung cancers and mesothelioma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3537. doi:10.1158/1538-7445.AM2011-3537