Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer

• Published in: Nature medicine Vol. 18; no. 2; pp. 221 - 223
• Main Authors: Montagut, Clara, Dalmases, Alba, Bellosillo, Beatriz, Crespo, Marta, Pairet, Silvia, Iglesias, Mar, Salido, Marta, Gallen, Manuel, Marsters, Scot, Tsai, Siao Ping, Minoche, André, Seshagiri, Somasekar, Serrano, Sergi, Himmelbauer, Heinz, Bellmunt, Joaquim, Rovira, Ana, Settleman, Jeff, Bosch, Francesc, Albanell, Joan
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2012; Nature Publishing Group
• Subjects: 692/699/67/1059/2326; 692/699/67/1504/1885; 692/699/67/1857; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; Antineoplastic Agents - therapeutic use; Biomedical and Life Sciences; Biomedicine; brief-communication; Cancer Research; Cell Line, Tumor; Cetuximab; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Development and progression; Drug resistance; Drug Resistance, Neoplasm - genetics; Epitopes - genetics; Humans; Infectious Diseases; Metabolic Diseases; Metastasis; Molecular Medicine; Mutation; Mutation, Missense - genetics; Neurons; Neurosciences; Quinazolines - therapeutic use; Receptor, Epidermal Growth Factor - genetics; Spain
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.2609

By modeling acquired resistance to the EGFR antibody cetuximab in metastatic colorectal cancer, the authors identify a new mutation in the ectodomain of the receptor. The mutation is present in patient tumors after cetuximab therapy, confirming that it represents a clinically-relevant mechanism for therapy resistance. Moreover, the mutation does not affect the response to other EGFR antibodies, suggesting that if independently confirmed it may be a useful indicator to tailor anti-EGFR therapy. Antibodies against epidermal growth factor receptor (EGFR)—cetuximab and panitumumab—are widely used to treat colorectal cancer. Unfortunately, patients eventually develop resistance to these agents. We describe an acquired EGFR ectodomain mutation (S492R) that prevents cetuximab binding and confers resistance to cetuximab. Cells with this mutation, however, retain binding to and are growth inhibited by panitumumab. Two of ten subjects studied here with disease progression after cetuximab treatment acquired this mutation. A subject with cetuximab resistance harboring the S492R mutation responded to treatment with panitumumab.