Investigation of the mechanisms and therapeutic implications of crosstalk between G-protein-coupled receptors and the epidermal growth factor receptor in HNSCC

摘要: Head and neck squamous cell carcinoma (HNSCC) is characterized by the overexpression of epidermal growth factor receptor. However, molecular targeting strategies against EGFR have not improved 5-year survival rates HNSCC patients. tyrosine kinase inhibitors displayed limited clinical responses in Phase II trials FDA-approved monoclonal antibody cetuximab (C225) did prevent occurrence secondary tumors distant metastases. G-protein-coupled receptor ligands; gastrin-releasing peptide (GRP), prostaglandin E2 (PGE2) bradykinin (BK) all been reported to activate via extracellular release ligands TGF-a AR. To improve efficacy inhibition HNSCC, we investigated common signaling intermediates involved GPCR-EGFR crosstalk. We previously that GRP mediated phosphoinositide-dependent 1 (PDK1) - dependent phosphorylation a disintegrin metalloprotease 17 (ADAM17). subsequently whether PDK1 mediates activation downstream PGE2, BK LPA pathways different HNSCC. LPA-mediated was abrogated siRNA-transfected cells. siRNA also decreased PGE2 BK-mediated vitro. Expression kinase-dead (PDK1M) -mediated growth. PDK1M cells demonstrated reduced proliferation compared control nanomolar sensitivity inhibitor OSU-03012 normal mucosal Combined treatment with TKIs erlotinib or AG1478, plus enhanced anti-proliferative effects. MAPK presence inhibition, combined GPCR additive synergistic anti-tumor elucidate EGFR-independent GPCRs, used forward phase phosphoprotein array identify potential targets can potentiate inhibition. observed p70S6K induced sustained (C225)-treated following stimulation. Further investigation showed downmodulation on PKCa expression. mTOR RAD001 GPCR-mediated vitro vivo. The results from this study indicated conjunction may be beneficial therapeutic for subset patients respond poorly treatment.