• Clin Cancer Res · Oct 2010

    Synergistic antitumor activity of sorafenib in combination with epidermal growth factor receptor inhibitors in colorectal and lung cancer cells.

    • Erika Martinelli, Teresa Troiani, Floriana Morgillo, Gabriella Rodolico, Donata Vitagliano, Maria Pia Morelli, Concetta Tuccillo, Loredana Vecchione, Anna Capasso, Michele Orditura, Ferdinando De Vita, S Gail Eckhardt, Massimo Santoro, Liberato Berrino, and Fortunato Ciardiello.
    • Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale F Magrassi e A Lanzara, Seconda Università degli Studi di Napoli, Napoli, Italy.
    • Clin Cancer Res. 2010 Oct 15; 16 (20): 4990-5001.

    PurposeCancer cell survival, invasion, and metastasis depend on cancer cell proliferation and on tumor-induced angiogenesis. We evaluated the efficacy of the combination of sorafenib and erlotinib or cetuximab.Experimental DesignSorafenib, erlotinib, and cetuximab, alone or in combination, were tested in vitro in a panel of non-small cell lung cancer (NSCLC) and colorectal cancer cell lines and in vivo in H1299 tumor xenografts.ResultsEpidermal growth factor receptor (EGFR) ligand mRNAs were expressed in all NSCLC and colorectal cancer cell lines with variable levels ranging from 0.4- to 8.1-fold as compared with GEO colorectal cancer cells. Lung cancer cells had the highest levels of vascular endothelial growth factors (VEGF) A, B, and C, and of VEGF receptors as compared with colorectal cancer cells. Combined treatments of sorafenib with erlotinib or cetuximab produced combination index values 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 mitogen-activated protein kinase 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 to 90 days increase in mice median overall survival as compared with single-agent sorafenib treatment.ConclusionsCombination treatment with sorafenib and erlotinib or cetuximab has synergistic antitumor effects in human colorectal and lung cancer cells.

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