Afatinib against esophageal or head-and-neck squamous cell carcinoma: Significance of activating oncogenic HER4 mutations in HNSCC

Yu Nakamura, Yosuke Togashi, Hirokazu Nakahara, Shuta Tomida, Eri Banno, Masato Terashima, Hidetoshi Hayashi, Marco A. De Velasco, Kazuko Sakai, Yoshihiko Fujita, Takatsugu Okegawa, Kikuo Nutahara, Suguru Hamada, Kazuto Nishio

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8 Citations (Scopus)

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 cellline, 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.

Original languageEnglish
Pages (from-to)1988-1997
Number of pages10
JournalMolecular cancer therapeutics
Volume15
Issue number8
DOIs
Publication statusPublished - Aug 2016
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Nakamura, Y., Togashi, Y., Nakahara, H., Tomida, S., Banno, E., Terashima, M., Hayashi, H., De Velasco, M. A., Sakai, K., Fujita, Y., Okegawa, T., Nutahara, K., Hamada, S., & Nishio, K. (2016). Afatinib against esophageal or head-and-neck squamous cell carcinoma: Significance of activating oncogenic HER4 mutations in HNSCC. Molecular cancer therapeutics, 15(8), 1988-1997. https://doi.org/10.1158/1535-7163.MCT-15-0737