title: The anti-HER3 antibody patritumab abrogates cetuximab resistance mediated by heregulin in colorectal cancer cells.
abstract: We previously showed that tumor-derived heregulin, a ligand for HER3, is associated with both de novo and acquired resistance to cetuximab. We have now examined whether patritumab, a novel neutralizing monoclonal antibody to HER3, is able to overcome such resistance. Human colorectal cancer (DiFi) cells that are highly sensitive to cetuximab were engineered to stably express heregulin by retroviral infection, and the effects of cetuximab and patritumab on the resulting DiFi-HRG cells were examined. DiFi-HRG cells released substantial amounts of heregulin and showed resistance to cetuximab. Cetuximab alone inhibited EGFR and ERK phosphorylation in DiFi-HRG cells, but it had no effect on the phosphorylation of HER2, HER3, or AKT, suggesting that sustained AKT activation by HER2 and HER3 underlies cetuximab resistance in these cells. In contrast, patritumab in combination with cetuximab markedly inhibited the phosphorylation of EGFR, HER2, HER3, ERK, and AKT. The combination therapy also inhibited the growth of DiFi-HRG tumor xenografts in nude mice to a greater extent than did treatment with either drug alone. Activation of HER2-HER3 signaling associated with the operation of a heregulin autocrine loop confers resistance to cetuximab, and patritumab is able to restore cetuximab sensitivity through inhibition of heregulin-induced HER3 activation.
authors.affiliation: Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka-sayama, Osaka 589-8511, Japan.
authors.forename: Hisato
authors.initials: H
authors.lastname: Kawakami
authors.affiliation: Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka-sayama, Osaka 589-8511, Japan. Center for Clinical and Translational Research, Kyushu University Hospital, Higashiku, Fukuoka 812-8582, Japan.
authors.forename: Isamu
authors.initials: I
authors.lastname: Okamoto
authors.affiliation: Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka-sayama, Osaka 589-8511, Japan.
authors.forename: Kimio
authors.initials: K
authors.lastname: Yonesaka
authors.affiliation: Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka-sayama, Osaka 589-8511, Japan.
authors.forename: Kunio
authors.initials: K
authors.lastname: Okamoto
authors.affiliation: Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka-sayama, Osaka 589-8511, Japan.
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Shibata
authors.affiliation: Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka-sayama, Osaka 589-8511, Japan.
authors.forename: Yume
authors.initials: Y
authors.lastname: Shinkai
authors.affiliation: Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka-sayama, Osaka 589-8511, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Sakamoto
authors.affiliation: Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka-sayama, Osaka 589-8511, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Kitano
authors.affiliation: Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka-sayama, Osaka 589-8511, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Tamura
authors.affiliation: Department of Genome Biology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
authors.affiliation: Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka-sayama, Osaka 589-8511, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakagawa
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000080908:Broadly Neutralizing Antibodies; D045744:Cell Line, Tumor; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000473:pathology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D020890:Neuregulin-1 / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D000970:Antineoplastic Agents; D000080908:Broadly Neutralizing Antibodies; C094131:NRG1 protein, human; D020890:Neuregulin-1; C585471:patritumab; C581292:ERBB3 protein, human; D020893:Receptor, ErbB-3; D000068818:Cetuximab