The prognosis for patients with head-and neck or esophageal squamous cell carcinoma (HNSCC or ESCC) remains poor. Thus, this study was performed to identify additional oncogenes coupled with the inhibitors.
We evaluated the sensitivity to HER inhibitors (cetuximab, erlotinib, and afatinib) in several HNSCC and ESCC cell lines in vitro. In the hypersensitive cell lines, the mechanisms such as gene mutation and amplification were investigated. Furthermore, the frequencies of the identified mechanisms were analyzed using the databases of HNSCC and ESCC.
Two of 12 HNSCC or ESCC cell lines that were hypersensitive to afatinib were identified, whereas no cell line was sensitive to cetuximab or erlotinib. The sequence analyses for the afatinib targeted genes, HER family, in the two cell lines revealed that one cell line had a HER4 mutation whose function had not been investigated, while another had a previously reported activating EGFR mutation. No amplification of HER family gene was found in the two cell lines. The phosphorylation level of HER4 was elevated in the HER4 mutation-overexpressed HEK293 cell line, and the mutation had a transforming potential in the NIH3T3 cell line, indicating that this HER4 mutation is an activating oncogenic mutation. Afatinib dramatically reduced the phosphorylation of EGFR or HER4 and induced apoptosis in the two cell lines. In vivo, tumor growth was also dramatically decreased by afatinib. In the databases, the frequencies of HER family mutations in HNSCC or ESCC ranged from 0% to 5%. Particularly, HER4 mutations have been found relatively frequently in HNSCC.
Considering the addiction of cancer cells to activating EGFR or HER4 mutations for proliferation, HNSCC or ESCC with such oncogenic mutations might be suitable for targeted therapy with afatinib.
Clinical trial identification
All authors have declared no conflicts of interest.