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Afatinib against Esophageal or Head-and-Neck Squamous Cell Carcinoma: Significance of Activating Oncogenic HER4 Mutations in HNSCC.
- Source :
-
Molecular cancer therapeutics [Mol Cancer Ther] 2016 Aug; Vol. 15 (8), pp. 1988-97. Date of Electronic Publication: 2016 May 20. - Publication Year :
- 2016
-
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.<br /> (©2016 American Association for Cancer Research.)
- Subjects :
- Afatinib
Animals
Apoptosis drug effects
Apoptosis genetics
Carcinoma, Squamous Cell drug therapy
Carcinoma, Squamous Cell metabolism
Cell Line, Tumor
Cell Survival drug effects
Disease Models, Animal
Dose-Response Relationship, Drug
ErbB Receptors genetics
ErbB Receptors metabolism
Esophageal Neoplasms drug therapy
Esophageal Neoplasms metabolism
Female
HEK293 Cells
Head and Neck Neoplasms drug therapy
Head and Neck Neoplasms metabolism
Humans
Mice
Multigene Family
NIH 3T3 Cells
Phosphorylation
Receptor, ErbB-4 metabolism
Signal Transduction drug effects
Squamous Cell Carcinoma of Head and Neck
Xenograft Model Antitumor Assays
Antineoplastic Agents pharmacology
Carcinoma, Squamous Cell genetics
Cell Transformation, Neoplastic genetics
Esophageal Neoplasms genetics
Head and Neck Neoplasms genetics
Mutation
Quinazolines pharmacology
Receptor, ErbB-4 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1538-8514
- Volume :
- 15
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Molecular cancer therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 27207775
- Full Text :
- https://doi.org/10.1158/1535-7163.MCT-15-0737