Importance of the Field The epidermal growth factor receptor (EGFR) is an established therapeutic target in head and neck squamous cell carcinoma (HNSCC). The EGFR-targeting monoclonal antibody cetuximab (™Erbitux) was FDA-approved for use in HNSCC in 2006. The molecular basis for the efficacy of an antibody approach compared with inhibition of EGFR tyrosine kinase function using small molecule inhibitors, or downregulation of protein expression via antisense strategies remains incompletely understood. Areas covered in this review A literature search was performed to identify studies elucidating mechanisms of action of several approaches to targeting EGFR in HNSCC (monoclonal antibodies, tyrosine kinase inhibitors, antisense approaches, and ligand toxin conjugates). What the reader will gain Monoclonal antibodies decrease tumor growth via receptor endocytosis and recruitment of host immune defenses. Tyrosine kinase inhibitors bind to the ATP binding pocket of the tyrosine kinase domain, inhibiting signaling. Antisense approaches decrease EGFR expression with high specificity although drug delivery remains problematic. Ligand-toxin conjugates facilitate the entry of toxin and the ADP-ribosylation of the ribosome, thereby inhibiting translation. Take home message Elucidation mechanisms by which these different strategies inhibit EGFR function may enhance the development of more effective treatments for HNSCC and enable prospective identification of individuals who will benefit from EGFR inhibition.
Head and neck squamous cell carcinoma (HNSCC) is characterized by overexpression of the epidermal growth factor receptor (EGFR) where treatments targeting EGFR have met with limited clinical success. Elucidation of the key downstream-pathways that remain activated in the setting of EGFR blockade may reveal new therapeutic targets. The present study was undertaken to test the hypothesis that inhibition of the mammalian target of rapamycin (mTOR) complex would enhance the effects of EGFR blockade in HNSCC preclinical models. Treatment of HNSCC cell lines with the newly developed TORC1/TORC2 inhibitor OSI-027/ASP4876 resulted in dose-dependent inhibition of proliferation with abrogation of phosphorylation of known downstream targets including phospho-AKT (Ser473), phospho-4E-BP1, phospho-p70s6K, and phospho-PRAS40. Furthermore, combined treatment with OSI-027 and erlotinib resulted in enhanced biochemical effects and synergistic growth inhibition in vitro. Treatment of mice bearing HNSCC xenografts with a combination of the Food and Drug Administration (FDA)-approved EGFR inhibitor cetuximab and OSI-027 demonstrated a significant reduction of tumor volumes compared with either treatment alone. These findings suggest that TORC1/TORC2 inhibition in conjunction with EGFR blockade represents a plausible therapeutic strategy for HNSCC.
G-protein-coupled receptors (GPCRs) activate the epidermal growth factor receptor (EGFR) and mediate EGFR-independent signaling pathways to promote the growth of a variety of cancers including head and neck squamous cell carcinoma (HNSCC). Identification of the common signaling mechanisms involved in GPCR-induced EGFR-dependent and independent processes will facilitate the development of more therapeutic strategies. In this study, we hypothesized that phosphoinositide-dependent kinase 1 (PDK1) contributes to GPCR-EGFR crosstalk and signaling in the absence of EGFR and suggests that inhibition of the PDK1 pathway may be effective in the treatment of HNSCC. The contribution of PDK1 to the EGFR-dependent and independent signaling in HNSCC was determined using RNAi, a kinase-dead mutant and pharmacological inhibition. In vivo xenografts studies were also performed to determine the efficacy of targeting PDK1 alone or in combination with the FDA-approved EGFR inhibitor cetuximab. PDK1 contributed to both GPCR-induced EGFR activation and cell growth. PDK1 also mediated activation of p70S6K in the absence of EGFR. Blockade of PDK1 with a small molecule inhibitor (AR-12) abrogated HNSCC growth, induced apoptosis and enhanced the anti-proliferative effects of EGFR tyrosine kinase inhibitors in vitro. HNSCC xenografts expressing kinase-dead PDK1 demonstrated increased sensitivity to cetuximab compared to vector-transfected controls. Administration of AR-12 substantially decreased HNSCC tumor growth in vivo. These cumulative results demonstrate that PDK1 is a common signaling intermediate in GPCR-EGFR crosstalk and EGFR-independent signaling, and where targeting the PDK1 pathway may represent a rational therapeutic strategy to enhance clinical responses to EGFR inhibitors in HNSCC.
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