title: Anti-HER3 monoclonal antibody patritumab sensitizes refractory non-small cell lung cancer to the epidermal growth factor receptor inhibitor erlotinib.
abstract: Human epidermal growth factor receptor (HER) 3 is aberrantly overexpressed and correlates with poor prognosis in non-small cell lung cancer (NSCLC). Patritumab is a monoclonal antibody against HER3 that has shown promising results in early-phase clinical trials, but an optimal target population for the drug has yet to be identified. In the present study, we examined whether heregulin, a HER3 ligand that is also overexpressed in a subset of NSCLC, can be used as a biomarker to predict the antitumorigenic efficacy of patritumab and whether the drug can overcome the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) resistance induced by heregulin. Patritumab sensitivity was associated with heregulin expression, which, when abolished, resulted in the loss of HER3 and AKT activation and growth arrest. Furthermore, heregulin overexpression induced EGFR TKI resistance in NSCLC cells harbouring an activating EGFR mutation, while HER3 and AKT activation was maintained in the presence of erlotinib in heregulin-overexpressing, EGFR-mutant NSCLC cells. Sustained HER3-AKT activation was blocked by combining erlotinib with either anti-HER2 or anti-HER3 antibody. Notably, heregulin was upregulated in tissue samples from an NSCLC patient who had an activating EGFR mutation but was resistant to the TKI gefitinib. These results indicate that patritumab can overcome heregulin-dependent EGFR inhibitor resistance in NSCLC in vitro and in vivo and suggest that it can be used in combination with EGFR TKIs to treat a subset of heregulin-overexpressing NSCLC patients.
authors.affiliation: Department of Medical Oncology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yonesaka
authors.affiliation: Daiichi-Sankyo Pharmaceutical Development, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Hirotani
authors.affiliation: Department of Medical Oncology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kawakami
authors.affiliation: Department of Medical Oncology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Takeda
authors.affiliation: Department of Medical Oncology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kaneda
authors.affiliation: Department of Genome Biology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Sakai
authors.affiliation: Center for Clinical and Translational Research, Kyushu University, Fukuoka, Japan.
authors.forename: I
authors.initials: I
authors.lastname: Okamoto
authors.affiliation: Department of Genome Biology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Nishio
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.|Department of Medicine, Brigham Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Jänne
authors.affiliation: Department of Medical Oncology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Nakagawa
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D000080908:Broadly Neutralizing Antibodies; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology; D005260:Female; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D051379:Mice; D020890:Neuregulin-1 / Q000378:metabolism; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors; D014162:Transfection
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; D034741:RNA, Small Interfering; C585471:patritumab; D000069347:Erlotinib Hydrochloride; C581292:ERBB3 protein, human; D066246:ErbB Receptors; D020893:Receptor, ErbB-3