Synergistic Antitumor Activity of Sorafenib in Combination with Epidermal Growth Factor Receptor Inhibitors in Colorectal and Lung Cancer Cells.

PURPOSE: Cancer cell survival, invasion and metastasis depend on cancer cell proliferation and on tumor-induced angiogenesis. We have evaluated the efficacy of the combination of sorafenib, and erlotinib or cetuximab EXPERIMENTAL DESIGN: sorafenib, erlotinib and cetuximab alone or in combination were tested in vitro in a panel of human lung (NSCLC) and colon cancer (CRC) cell lines and in vivo in H1299 tumor xenografts. RESULTS: EGFR ligands mRNAs were expressed in all NSCLC and CRC cell lines with variable levels ranging between 0.4-8.1 folds as compared to GEO CRC cells. Lung cancer cells had the highest levels of VEGF-A-B-C and of VEGFRs as compared to colorectal cancer cells. Combined treatments of sorafenib with erlotinib or cetuximab produced CI (combination index) values ranged between 0.02 and 0.5, suggesting a significant synergistic activity to inhibit soft agar colony formation in all cancer cell lines which was accompanied by a marked blockade in MAPK- and AKT signals. The in vitro migration of H1299 cells, which expressed high levels of both VEGF ligands and receptors, was inhibited by treatment with sorafenib and this effect was significantly increased by the combination with anti-EGFR drugs. In nude mice bearing established human H1299 xenografts, treatment with the combination of sorafenib and erlotinib or cetuximab caused a significant tumor growth delay resulting in 70-90 days increase in mice median overall survival as compared to single agent sorafenib treatment. CONCLUSIONS: Combination treatment with sorafenib and erlotinib or cetuximab has synergistic antitumor effects in human colorectal and lung cancer cells.