Adaptive ERK1/2 signalling as a response to HNSCC therapy

Introduction Patients with head and neck squamous cell carcinoma (HNSCC) frequently develop resistance to irradiation (IR) and treatment with cetuximab, an EGFR monoclonal antibody. We addressed the regulation of MAP kinase ERK1/2 by cetuximab and fractionated IR and performed a prognostic in silico evaluation of the EGFR-MAPK axis in HNSCC.

Methods The expression of phosphorylated ERK1/2 (pERK1/2) was determined in fractionally irradiated and / or cetuximab-treated established HNSCC cell lines. The effect of pERK1/2 modulation was validated in vital HNSCC tissue cultures. The prognostic significance of the EGFR-ERK axis was evaluated by TMA including HNSCC patient samples treated with IR plus cetuximab. In addition, possible correlations between EGFR-MAPK signalling factors and the association between transcript and protein expression profiles and survival of HNSCC patients were analyzed using publicly available databases.

Results Fractionated IR induced the phosphorylation of ERK1/2, which, however, could be suppressed by the radiosensitizing effect of pharmacological MEK inhibition. After prolonged administration of cetuximab, there was a rebound of previously suppressed ERK1/2 activation. In silico assessments as well as TMA results suggested that EGFR-MAPK cascade genes and proteins could predict HNSCC patients survival as a prognostic signature.

Conclusions We hypothesize that adaptive activation of ERK1/2 contributes to the resistance of HNSCC to cetuximab and IR. The EGFR MAPK axis appears as a relevant prognosticator for this tumor entity.

Poster-PDF A-1086.PDF

Publication History

Article published online:
10 June 2020