Epidermal growth factor receptor inhibitor induces Interleukin-6 via NADPH oxidase enzymes in head and neck cancer cells

The epidermal growth factor receptor (EGFR) is a tyrosine kinase cell surface receptor, belonging to the ErbB family of receptors, which functions to initiate downstream signaling pathways resulting in cellular proliferation, differentiation, migration, adhesion, and metastasis. EGFR is over expressed in numerous types of cancers including head and neck, breast, colon, lung, renal, and ovarian, and this overexpression of EGFR has been correlated with poor prognosis and survival rates specifically in head and neck squamous cell carcinoma (HNSCC). Due to the pro-oncogenic activity of EGFR (e.g. cell growth, angiogenesis, and metastasis), ameliorating the function of EGFR makes it an attractive target for chemotherapy. While clinical therapy with Erlotinib is quite successful, resistance to the chemotherapy agent is highly prevalent. To date, the molecular mechanism by which cancers become resistant to Erlotinib remains unclear. Here we show a novel pathway in head and neck carcinoma cell lines involving the up-regulation of NADPH oxidase enzymes (NOX) after Erlotinib treatment, which leads to an increased production of hydrogen peroxide and finally increased IL-6 production. The IL-6 axis has been proposed to play a definitive role in the long-term proliferation and survival of various cancers, and perturbation of this axis by Erlotinib may initiate pro-survival signals which render the cancers resistant to Erlotinib. Therefore, we put forth a model of multidrug therapy targeting NOX enzymes and/or IL-6 in combination with Erlotinib to counteract the potential drug-resistance mechanisms often observed in malignancy.