Abstract
Head and neck cancer stem cells (CSCs) are highly resistant to treatment. When EGFR is overexpressed in head and neck squamous cell carcinoma (HNSCC), HER2 and HER3 are also expressed. The aim of the present study was to investigate the effect of HER1/2/3 blockade through a combination of cetuximab and pertuzumab, with or without photon irradiation, on the proliferation and migration/invasion capabilities of an HNSCC chemo- and radioresistant human cell line (SQ20B) and its corresponding stem cell subpopulation. Cell proliferation, migration and invasion were studied after treatment with cetuximab +/− pertuzumab +/− 10 Gy photon irradiation. EGFR, phospho-EGFR, HER2 and HER3 protein expression levels were studied. Activation or inhibition of the RAS/MAPK and AKT-mTOR downstream signalling cascades was investigated through phospho-AKT and phospho-MEK1/2 expression. Cetuximab strongly inhibited SQ20B and FaDu cell proliferation, migration and invasion, whereas it had little effect on SQ20B-CSCs. Cetuximab–pertuzumab combined with radiation significantly inhibited SQ20B and FaDu cell and SQ20B-CSC proliferation, migration and invasion. Cetuximab–pertuzumab with 10 Gy photon irradiation switched off both phospho-AKT and phospho-MEK1/2 expression in the three populations. The triple therapy is therefore thought to inhibit SQ20B cells, SQ20B-CSCs and FaDu cells through an AKT-mTOR and Ras-MAPK downstream signalling blockade.
Highlights
Head and neck cancer stem cells (CSCs) are highly resistant to treatment
Pertuzumab is an HER2 antagonist directed against the extracellular dimerization domain, and which blocks the ligand-dependent heterodimerization of HER2 with other human epidermal growth factor receptor (HER) family members, including epidermal growth factor receptor (EGFR) or HER1, HER3 and HER4
EGFR was highly overexpressed in SQ20B cells, the opposite occurred in SQ20B-CSCs and FaDu cells, in which EGFR was expressed at much lower levels (P < 0.001)
Summary
Head and neck cancer stem cells (CSCs) are highly resistant to treatment. When EGFR is overexpressed in head and neck squamous cell carcinoma (HNSCC), HER2 and HER3 are expressed. In the past few years, it has been shown that the epidermal growth factor receptor (EGFR) is overexpressed in more than 90% of HNSCCs2 Faced with this therapeutic target, cetuximab, a mouse– human chimeric monoclonal antibody directed against EGFR, was developed and shown to significantly improve locoregional control, progression-free survival and overall survival when used concomitantly with radiotherapy (RT)[3,4]. With a central role being played by human epidermal growth factor receptor (HER) family members (HER2 or erbB2, HER3 or erbB3, HER4 or erbB4)[10] These receptors activate downstream signalling cascades including MAPK and PI3K/AKT through ligand-dependent homo- or heterodimerization, and enhance cell proliferation, angiogenesis, invasion and metastasis. The aim of the present study was to explore the effect of a pan-HER blockade on the proliferation, migration and invasion of human HNSCC cells and their corresponding CSC subpopulation, through combined treatment with cetuximab and pertuzumab, with or without photon irradiation
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