title: Afatinib against Esophageal or Head-and-Neck Squamous Cell Carcinoma: Significance of Activating Oncogenic HER4 Mutations in HNSCC.
abstract: The prognosis for patients with advanced esophageal or head-and-neck squamous cell carcinoma (ESCC or HNSCC) remains poor, and the identification of additional oncogenes and their inhibitors is needed. In this study, we evaluated the sensitivities of several ESCC and HNSCC cell lines to HER inhibitors (cetuximab, erlotinib, and afatinib) in vitro and found two cell lines that were hypersensitive to afatinib. Sequence analyses for the afatinib-targeted HER family genes in the two cell lines revealed that one cell line had a previously reported activating EGFR L861Q mutation, whereas the other had an HER4 G1109C mutation of unknown function. No amplification of HER family genes was found in either of the two cell lines. The phosphorylation level of HER4 was elevated in the HER4 G1109C mutation-overexpressed HEK293 cell line, and the mutation had a transforming potential and exhibited tumorigenicity in an NIH3T3 cell line, indicating that this HER4 mutation was an activating oncogenic mutation. Afatinib dramatically reduced the phosphorylation level of EGFR or HER4 and induced apoptosis in the two cell lines. In vivo, tumor growth was also dramatically decreased by afatinib. In a database, the frequencies of HER family gene mutations in ESCC or HNSCC ranged from 0% to 5%. In particular, HER4 mutations have been found relatively frequently in HNSCC. Considering the addiction of cancer cells to activating oncogenic EGFR or HER4 mutations for proliferation, HNSCC or ESCC with such oncogenic mutations might be suitable for targeted therapy with afatinib. Mol Cancer Ther; 15(8); 1988-97. ©2016 AACR.
authors.affiliation: Department of Genome Biology, Kindai University Faculty of Medicine, Osaka, Japan. Department of Urology, Kyorin University School of Medicine, Tokyo, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Department of Genome Biology, Kindai University Faculty of Medicine, Osaka, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Togashi
authors.affiliation: Department of Oral and Maxillofacial Surgery, Kindai University Faculty of Medicine, Osaka, Japan. Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Osaka City University, Osaka, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Nakahara
authors.affiliation: Department of Genome Biology, Kindai University Faculty of Medicine, Osaka, Japan.
authors.forename: Shuta
authors.initials: S
authors.lastname: Tomida
authors.affiliation: Department of Genome Biology, Kindai University Faculty of Medicine, Osaka, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Banno
authors.affiliation: Department of Genome Biology, Kindai University Faculty of Medicine, Osaka, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Terashima
authors.affiliation: Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Hayashi
authors.affiliation: Department of Genome Biology, Kindai University Faculty of Medicine, Osaka, Japan.
authors.forename: Marco A
authors.initials: MA
authors.lastname: de Velasco
authors.affiliation: Department of Genome Biology, Kindai University Faculty of Medicine, Osaka, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Sakai
authors.affiliation: Department of Genome Biology, Kindai University Faculty of Medicine, Osaka, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Fujita
authors.affiliation: Department of Urology, Kyorin University School of Medicine, Tokyo, Japan.
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Okegawa
authors.affiliation: Department of Urology, Kyorin University School of Medicine, Tokyo, Japan.
authors.forename: Kikuo
authors.initials: K
authors.lastname: Nutahara
authors.affiliation: Department of Oral and Maxillofacial Surgery, Kindai University Faculty of Medicine, Osaka, Japan.
authors.forename: Suguru
authors.initials: S
authors.lastname: Hamada
authors.affiliation: Department of Genome Biology, Kindai University Faculty of Medicine, Osaka, Japan. knishio@med.kindai.ac.jp.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
mesh_terms: D000077716:Afatinib; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D005810:Multigene Family; D009154:Mutation; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011799:Quinazolines / Q000494:pharmacology*; D066247:Receptor, ErbB-4 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077195:Squamous Cell Carcinoma of Head and Neck; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D000077716:Afatinib; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4