Adaptive ERK signalling activation in response to therapy and in silico prognostic evaluation of EGFR-MAPK in HNSCC

Autor: Annette Affolter, Fang Xiang, Marie Muller, Jochen Hess, Peter K. Plinkert, Wilko Weichert, Alexandra D Jensen, Gerald Major, Chao Rong
Rok vydání: 2020
Předmět:
MAPK/ERK pathway
Cancer Research
MAP Kinase Signaling System
medicine.medical_treatment
Cetuximab
Antibodies
Monoclonal
Humanized
Article
Mice
Prognostic markers
03 medical and health sciences
0302 clinical medicine
stomatognathic system
Cell Line
Tumor
otorhinolaryngologic diseases
Animals
Humans
Medicine
Head and neck cancer
Protein Kinase Inhibitors
neoplasms
030304 developmental biology
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase Kinases
0303 health sciences
Molecular medicine
Squamous Cell Carcinoma of Head and Neck
business.industry
Kinase
MEK inhibitor
Prognosis
medicine.disease
Xenograft Model Antitumor Assays
Head and neck squamous-cell carcinoma
ddc
ErbB Receptors
Radiation therapy
stomatognathic diseases
Oncology
Drug Resistance
Neoplasm
030220 oncology & carcinogenesis
Monoclonal
Cancer research
Insect Proteins
business
Ex vivo
medicine.drug
Zdroj: British Journal of Cancer
ISSN: 1532-1827
0007-0920
Popis: Background Head 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. Methods Expression 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. Results ERK1/2 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. Conclusions Activation 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.
Databáze: OpenAIRE
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