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Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer.

Regales L, Gong Y, Shen R, de Stanchina E, Vivanco I, Goel A, Koutcher JA, Spassova M, Ouerfelli O, Mellinghoff IK, Zakowski MF, Politi KA, Pao W
J Clin Invest. 2009 119 (10): 3000-10

PMID: 19759520 · PMCID: PMC2752070 · DOI:10.1172/JCI38746

EGFR is a major anticancer drug target in human epithelial tumors. One effective class of agents is the tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. These drugs induce dramatic responses in individuals with lung adenocarcinomas characterized by mutations in exons encoding the EGFR tyrosine kinase domain, but disease progression invariably occurs. A major reason for such acquired resistance is the outgrowth of tumor cells with additional TKI-resistant EGFR mutations. Here we used relevant transgenic mouse lung tumor models to evaluate strategies to overcome the most common EGFR TKI resistance mutation, T790M. We treated mice bearing tumors harboring EGFR mutations with a variety of anticancer agents, including a new irreversible EGFR TKI that is under development (BIBW-2992) and the EGFR-specific antibody cetuximab. Surprisingly, we found that only the combination of both agents together induced dramatic shrinkage of erlotinib-resistant tumors harboring the T790M mutation, because together they efficiently depleted both phosphorylated and total EGFR. We suggest that these studies have immediate therapeutic implications for lung cancer patients, as dual targeting with cetuximab and a second-generation EGFR TKI may be an effective strategy to overcome T790M-mediated drug resistance. Moreover, this approach could serve as an important model for targeting other receptor tyrosine kinases activated in human cancers.

MeSH Terms (30)

Afatinib Amphiregulin Animals Antibodies, Monoclonal Antibodies, Monoclonal, Humanized Antineoplastic Agents Cetuximab Disease Models, Animal Drug Resistance, Neoplasm EGF Family of Proteins Epidermal Growth Factor Epiregulin ErbB Receptors Erlotinib Hydrochloride Gene Expression Profiling Glycoproteins Humans Intercellular Signaling Peptides and Proteins Lung Neoplasms Male Mice Mice, Nude Mice, Transgenic Mutation Neoplasm Transplantation Paclitaxel Protein Kinase Inhibitors Quinazolines Transplantation, Heterologous Tumor Cells, Cultured

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