title: Co-treatment of wild-type EGFR head and neck cancer cell lines with afatinib and cisplatin.
abstract: Treatment of head and neck squamous cell carcinoma (HNSCC) remains challenging. Non‑surgical approaches typically comprise radiotherapy and antineoplastic chemotherapy, of which platinum‑based agents are the most common. Similar to other malignancies, targeted therapies have an increasing role in the treatment of head and neck cancer. The overexpression of epidermal growth factor receptor (EGFR) is a useful target for specific therapeutic strategies. Resistance to EGFR‑directed therapies, including cetuximab, is partly mediated by the activation of alternative receptors and pathways. Therefore, other members of the ErbB family, including human epidermal growth factor receptor (HER)2 and HER4, may have important therapeutic roles. The aim of the present study was to investigate the efficacy of afatinib, an EGFR/HER2/HER4 tyrosine kinase inhibitor, in combination with cisplatin in HNSCC cell lines. The cisplatin concentration used was set at cell line‑specific half maximal inhibitory concentration values. Since the vast majority of head and neck cancers do not exhibit any EGFR tyrosine kinase domain mutations, five human EGFR wild‑type HNSCC cell lines were used in the present study. For statistical analyses, non‑parametric Mann‑Whitney tests were conducted. The present study detected a concentration‑dependent efficacy of afatinib. In three out of the five cell lines (PCI‑9, PCI‑52 and PCI‑68), 0.625 µM afatinib in combination with cisplatin exerted significant antiproliferative effects. In the two other cell lines (PCI‑1 and PCI‑13), significant effects were observed following treatment with ≥1.25 µM afatinib. Notably, compared with the findings of previous studies, cell lines (PCI-9 and PCI-52) less vulnerable to erlotinib or gefitinib were more vulnerable to the afatinib/cisplatin combination, and vice versa. Differences in the treatment success of erlotinib/gefitinib (targeting only EGFR) and afatinib (targeting EGFR, HER2 and HER4) may be explained by mutations in the EGFR. Therefore, afatinib treatment may be considered an important therapeutic option for patients failing cetuximab treatment. In addition, the present study demonstrated significant enhancement of platinum‑based therapies upon the addition of various afatinib concentrations. These results provide preclinical evidence to advocate further in vivo studies and clinical trials.
authors.affiliation: Department of Oral and Maxillofacial Plastic Surgery, University Hospital Würzburg, D‑97070 Würzburg, Germany.
authors.forename: Roman C
authors.initials: RC
authors.lastname: Brands
authors.affiliation: Department of Oral and Maxillofacial Plastic Surgery, University Hospital Würzburg, D‑97070 Würzburg, Germany.
authors.forename: Urs D A
authors.initials: UD
authors.lastname: Müller-Richter
authors.affiliation: Department of Oral and Maxillofacial Plastic Surgery, University Hospital Würzburg, D‑97070 Würzburg, Germany.
authors.forename: Francesco
authors.initials: F
authors.lastname: De Donno
authors.affiliation: Department of Oral and Maxillofacial Plastic Surgery, University Hospital Würzburg, D‑97070 Würzburg, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Seher
authors.affiliation: Institute of Pathology, University Würzburg, D‑97080 Würzburg, Germany.
authors.forename: Grit
authors.initials: G
authors.lastname: Mutzbauer
authors.affiliation: Department of Oral and Maxillofacial Plastic Surgery, University Hospital Würzburg, D‑97070 Würzburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Linz
authors.affiliation: Department of Oral and Maxillofacial Plastic Surgery, University Hospital Würzburg, D‑97070 Würzburg, Germany.
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Kübler
authors.affiliation: Department of Oral and Maxillofacial Plastic Surgery, University Hospital Würzburg, D‑97070 Würzburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hartmann
mesh_terms: D000077716:Afatinib; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000378:metabolism*; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D020128:Inhibitory Concentration 50; D000072417:Protein Domains; D011799:Quinazolines / Q000494:pharmacology*; D016896:Treatment Outcome
chemical_list: D011799:Quinazolines; D000077716:Afatinib; C512478:EGFR protein, human; D066246:ErbB Receptors; D002945:Cisplatin