Adaptive ERK signalling activation in response to therapy and in silico prognostic evaluation of EGFR-MAPK in HNSCC.
Animals
Antibodies, Monoclonal, Humanized
/ pharmacology
Cell Line, Tumor
Cetuximab
/ pharmacology
Drug Resistance, Neoplasm
/ drug effects
ErbB Receptors
/ genetics
Humans
Insect Proteins
MAP Kinase Signaling System
/ drug effects
Mice
Mitogen-Activated Protein Kinase 1
/ genetics
Mitogen-Activated Protein Kinase Kinases
/ genetics
Prognosis
Protein Kinase Inhibitors
/ pharmacology
Squamous Cell Carcinoma of Head and Neck
/ genetics
Xenograft Model Antitumor Assays
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
26
08
2019
accepted:
23
04
2020
revised:
25
01
2020
pubmed:
20
5
2020
medline:
20
2
2021
entrez:
20
5
2020
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 32424150
doi: 10.1038/s41416-020-0892-9
pii: 10.1038/s41416-020-0892-9
pmc: PMC7374086
doi:
Substances chimiques
Antibodies, Monoclonal, Humanized
0
Insect Proteins
0
Protein Kinase Inhibitors
0
EGFR protein, Anopheles gambiae
EC 2.7.10.1
EGFR protein, human
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
MAPK1 protein, human
EC 2.7.11.24
Mitogen-Activated Protein Kinase 1
EC 2.7.11.24
Mitogen-Activated Protein Kinase Kinases
EC 2.7.12.2
Cetuximab
PQX0D8J21J
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
288-297Références
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