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Abstract
BackgroundHead and neck squamous cell carcinoma (HNSCC) patients frequently develop treatment resistance to cetuximab, a monoclonal antibody against EGFR, as well as radiotherapy. Here we addressed extracellular signal-regulated kinase 1/2 (ERK1/2) regulation by cetuximab or fractionated irradiation (IR) and conducted in silico prognostic evaluation of the EGFR-MAPK axis in HNSCC.MethodsExpression of ERK1/2 phosphorylation (pERK1/2) was determined in HNSCC cell lines, which were treated with cetuximab or fractionated-IR. Furthermore, the effect of fractionated IR on pERK1/2 was confirmed in an ex vivo HNSCC tissue culture model. Expression and prognostic significance of EGFR-ERK axis was evaluated in a cohort of radiotherapy plus cetuximab-treated HNSCC. Correlations among EGFR-MAPK signalling components and association between transcript and protein expression profiles and patient survival in HNSCC were analysed using publicly available databases.ResultsERK1/2 phosphorylation was rebounded by prolonged cetuximab administration and was induced by fractionated IR, which could be suppressed by a MEK inhibitor as a radiosensitiser. In silico assessments suggested that EGFR-MAPK cascade genes and proteins could predict HNSCC patients’ survival as a prognostic signature.ConclusionsActivation of ERK1/2 signalling contributes to the cellular defence of HNSCC against cetuximab and fractionated IR treatment. EGFR-MAPK axis has a prognostic significance in HNSCC.
Highlights
Head and neck squamous cell carcinoma (HNSCC) patients frequently develop treatment resistance to cetuximab, a monoclonal antibody against epidermal growth factor receptor (EGFR), as well as radiotherapy
These data demonstrate that most HNSCC cell lines adapt to prolonged cetuximab treatment concerning extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation
Cetuximab is the only targeted therapy that has been proven effective for the treatment of HNSCC in both locally advanced (LA) and R/M settings
Summary
Head and neck squamous cell carcinoma (HNSCC) patients frequently develop treatment resistance to cetuximab, a monoclonal antibody against EGFR, as well as radiotherapy. The epidermal growth factor receptor (EGFR) and its ligands promote the malignant behaviour of different tumours by cellular processes such as proliferation, differentiation, antiapoptotic signalling, angiogenesis, and metastasis.[1] EGFR is overexpressed in up to 90% of head and neck squamous cell carcinomas (HNSCC), associated with an unfavourable prognosis.[2] By EGFR phosphorylation intracellular signalling cascades, for example, Ras/Raf/MAPK (mitogen-initiated protein kinase) and PI3K/AKT (phosphatidylinositol 3-kinase) are activated, which mediate cellular proliferation and survival.[3,4]. It has been shown that the MAPK-ERK signalling pathway contributes to the lack of response to EGFR inhibition.[8,9] ERK activation by oncogenic effectors such as HRAS10 or MET11 has been postulated to trigger cetuximab resistance
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