Abstract LB-243: Cetuximab and Artesunate synergistically inhibit the invasion and distant metastasis of non-small cell lung cancer

Abstract

Abstract Cancer is a complex disease and multi step process evolving from malfunctions of molecules and their complex networks which regulate this process. The blockage of the cancer signalling network is crucial in the cancer treatment. In some cases, single drug therapy might not be comprehensive enough to inhibit the activity of secondary signals, feedback regulations and resistance to particular molecules, due to their abundant expression or activity. An understanding of these complex phenomena in cancer therapy for the benefit of patients is essential, especially since it bears the chance to establish novel concepts of combination drug therapy. In the present study, we have tried to find a compound combination to overcome resistance towards Cetuximab, which blocks ligand binding to the epidermal growth factor receptor (EGFR), in non-small cell lung cancer (NSCLC). The anti-malarial drug Artesunate (ART) has been shown to have a profound cytotoxic action against cancer cell lines, and we recently showed its anti-metastatic action in NSCLC. Initial screening experiments in NSCLC cell lines showed that Cetuximab sensitivity is positively correlated with the E-cadherin expression, whereas ART sensitivity was negatively associated with EGFR expression. A549 (high E-cadherin and EGFR, sensitive to Cetuximab alone and not sensitive to ART alone) and H1299 (no E-cadherin and medium EGFR, resistant to Cetuximab alone and sensitive to ART alone) were chosen as model cell lines for this study. Cell proliferation and colony formation assays were performed either with Cetuximab/ART alone or with the combination of both. Interestingly, Cetuximab alone was not able to reduce cell proliferation and colony formation significantly in comparison to ART. In contrast to that combination of both of the drugs able to reduce these phenomena significantly even more than ART alone (p≤0.05). Combination isobologram analysis for ART and Cetuximab showed a significantly reduced proliferation rate in both the tested cell lines. In vivo, chorioallantoic membrane (CAM) metastasis assays revealed that combinatorial treatment of the cells with both drugs significantly reduced primary tumor growth of A549 (p=0.01) and H1299 (p=0.02) cells, in contrast to the treatment by Cetuximab alone. Our findings suggest that ART is resensitizing Cetuximab resistant NSCLC cells for treatment with this antibody. Currently, our study will be completed by experiments to identified major molecules and signalling cascades mediating compound interaction and re-sensitization. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-243. doi:1538-7445.AM2012-LB-243