title: The pan-HER family tyrosine kinase inhibitor afatinib overcomes HER3 ligand heregulin-mediated resistance to EGFR inhibitors in non-small cell lung cancer.
abstract: Afatinib is a second generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) characterized as an irreversible pan-human EGFR (HER) family inhibitor. Afatinib remains effective for a subpopulation of patients with non-small cell lung cancer (NSCLC) with acquired resistance to first generation EGFF-TKIs such as erlotinib. Heregulin activates HER3 in an autocrine fashion and causes erlotinib resistance in NSCLC. Here we examine whether afatinib is effective against heregulin-overexpressing NSCLCs harboring EGFR activating mutations. Afatinib but not erlotinib decreased EGFR mutant NSCLC PC9HRG cell proliferation in vitro and in mouse xenografts. Afatinib inhibited phosphorylation of the cell signaling pathway proteins HER3, EGFR, HER2, and HER4, likely by prevention of trans-phosphorylation as HER3 kinase activity is inadequate for auto-phosphorylation. Afatinib, unlike erlotinib, inhibited AKT activation, resulting in elevated apoptosis in PC9HRG cells. Clinically, a subpopulation of 33 patients with EGFR mutations and NSCLC who had received first generation EGFR-TKIs exhibited elevated plasma heregulin levels compared to healthy volunteers; one of these achieved a response with afatinib therapy despite having previously developed erlotinib resistance. Afatinib can overcome heregulin-mediated resistance to erlotinib in EGFR mutant NSCLC. Further studies are necessary to determine whether heregulin can predict afatinib efficacy after development offirst generation EGFR-TKI resistance.
authors.affiliation: Department of Medical Oncology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Kimio
authors.initials: K
authors.lastname: Yonesaka
authors.affiliation: Department of Medical Oncology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Kudo
authors.affiliation: Department of Medical Oncology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Nishida
authors.affiliation: Department of Medical Oncology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Takahama
authors.affiliation: Department of Medical Oncology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Iwasa
authors.affiliation: Department of Medical Oncology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Department of Medical Oncology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Department of Medical Oncology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Takeda
authors.affiliation: Department of Medical Oncology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Kaneda
authors.affiliation: Center for Clinical and Translational Research, Kyushu University, Fukuoka, Kyushu, Japan.
authors.forename: Isamu
authors.initials: I
authors.lastname: Okamoto
authors.affiliation: Department of Genome Biology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
authors.affiliation: Department of Medical Oncology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakagawa
mesh_terms: D000077716:Afatinib; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008024:Ligands; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020890:Neuregulin-1 / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D020893:Receptor, ErbB-3 / Q000378:metabolism*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D008024:Ligands; C094131:NRG1 protein, human; D020890:Neuregulin-1; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077716:Afatinib; C581292:ERBB3 protein, human; D020893:Receptor, ErbB-3
keywords: afatinib; erlotinib; heregulin; human epidermal growth factor receptor; non-small cell lung cancer