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Ref Type Journal Article
PMID (27207775)
Authors Nakamura Y, Togashi Y, Nakahara H, Tomida S, Banno E, Terashima M, Hayashi H, de Velasco MA, Sakai K, Fujita Y, Okegawa T, Nutahara K, Hamada S, Nishio K
Title Afatinib against Esophageal or Head-and-Neck Squamous Cell Carcinoma: Significance of Activating Oncogenic HER4 Mutations in HNSCC.
Journal Vol Issue Date Pages Journal Short Title
Molecular cancer therapeutics 15 8 2016 Aug 1988-97 Mol Cancer Ther
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
ERBB4 G1109C missense gain of function ERBB4 G1109C lies within the cytoplasmic domain of the Erbb4 protein (UniProt.org). G1109C confers a gain of function to the Erbb4 protein as demonstrated by increased phosphorylation of Erbb4 compared to wild-type and the ability to transform cells (PMID: 27207775).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ERBB4 G1109C head and neck squamous cell carcinoma sensitive Afatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Gilotrif (afatinib) treatment induced apoptosis in head and neck squamous cell carcinoma cells harboring ERBB4 (HER4) G1109C in culture and inhibited tumor growth in cell line xenograft models (PMID: 27207775). 27207775
ERBB4 G1109C head and neck squamous cell carcinoma no benefit Erlotinib Preclinical - Cell culture Actionable In a preclinical study, head and neck squamous cell carcinoma cells harboring ERBB4 (HER4) G1109C were insensitive to treatment with Tarceva (erlotinib) in culture (PMID: 27207775). 27207775
ERBB4 G1109C head and neck squamous cell carcinoma no benefit Cetuximab Preclinical - Cell culture Actionable In a preclinical study, head and neck squamous cell carcinoma cells harboring ERBB4 (HER4) G1109C were insensitive to treatment with Erbitux (cetuximab) in culture (PMID: 27207775). 27207775