title: Primary resistance to cetuximab in a panel of patient-derived tumour xenograft models: activation of MET as one mechanism for drug resistance.
abstract: Cetuximab (Erbitux®) targets the epidermal growth factor receptor (EGFR) and is approved for treatment of colorectal and head and neck cancer. Despite wide expression of EGFR, only a subgroup of cancer patients responds to cetuximab therapy. In the present study we assessed the cetuximab response in vivo of 79 human patient-derived xenografts originating from five tumour histotypes. We analysed basic tumour characteristics including EGFR expression and activation, mutational status of KRAS, BRAF and NRAS, the expression of EGFR ligands and the activation of HER3 (ErbB3) and the hepatocyte growth factor receptor MET. Based on these results, a cetuximab response score including positive and negative factors affecting therapeutic response is proposed. Positive factors are high expression and activation of EGFR and its ligands epiregulin or amphiregulin, negative factors are markers for downstream pathway activation independent of EGFR. In cetuximab resistant NSCL adenocarcinoma LXFA 526 and LXFA 1647, overexpression due to gene amplification and strong activation of MET was identified. Knock-down of MET by siRNA in the corresponding cell lines showed that anchorage-independent growth and migration are dependent on MET. MET knock down sensitized LXFA 526L and LXFA 1647L to EGF. Combined treatments of a MET inhibitor and cetuximab were additive. Therefore, combination therapy of cetuximab and a MET inhibitor in selected lung cancer patients could be of high clinical significance.
authors.affiliation: Oncotest GmbH, Institute for Experimental Oncology, Am Flughafen 12-14, 79108 Freiburg, Germany.
authors.forename: Rebekka
authors.initials: R
authors.lastname: Krumbach
authors.forename: Julia
authors.initials: J
authors.lastname: Schüler
authors.forename: Michael
authors.initials: M
authors.lastname: Hofmann
authors.forename: Torsten
authors.initials: T
authors.lastname: Giesemann
authors.forename: Heinz-Herbert
authors.initials: HH
authors.lastname: Fiebig
authors.forename: Thomas
authors.initials: T
authors.lastname: Beckers
mesh_terms: D066258:Amphiregulin; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000068818:Cetuximab; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm; D066255:EGF Family of Proteins; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism; D066260:Epiregulin; D066246:ErbB Receptors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008024:Ligands; D051379:Mice; D009368:Neoplasm Transplantation; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000378:metabolism
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C587849:Areg protein, mouse; D066255:EGF Family of Proteins; C587880:EREG protein, human; D066260:Epiregulin; C587881:Ereg protein, mouse; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D020893:Receptor, ErbB-3; D000068818:Cetuximab