title: Targeting the sheddase activity of ADAM17 by an anti-ADAM17 antibody D1(A12) inhibits head and neck squamous cell carcinoma cell proliferation and motility via blockage of bradykinin induced HERs transactivation.
abstract: A disintegrin and metalloproteinase 17 (ADAM17) regulates key cellular processes including proliferation and migration through the shedding of a diverse array of substrates such as epidermal growth factor receptor (EGFR) ligands. ADAM17 is implicated in the pathogenesis of many diseases including rheumatoid arthritis and cancers such as head and neck squamous cell carcinoma (HNSCC). As a central mediator of cellular events, overexpressed EGFR is a validated molecular target in HNSCC. However, EGFR inhibition constantly leads to tumour resistance. One possible mechanism of resistance is the activation of alternative EGFR family receptors and downstream pathways via the release of their ligands. Here, we report that treating human HNSCC cells in vitro with a human anti-ADAM17 inhibitory antibody, D1(A12), suppresses proliferation and motility in the absence or presence of the EGFR tyrosine kinase inhibitor (TKI) gefitinib. Treatment with D1(A12) decreases both the endogenous and the bradykinin (BK)-stimulated shedding of HER ligands, accompanied by a reduction in the phosphorylation of HER receptors and downstream signalling pathways including STAT3, AKT and ERK. Knockdown of ADAM17, but not ADAM10, also suppresses HNSCC cell proliferation and migration. Furthermore, we show that heregulin (HRG) and heparin-binding epidermal growth factor like growth factor (HB-EGF) predominantly participate in proliferation and migration, respectively. Taken together, these results demonstrate that D1(A12)-mediated inhibition of cell proliferation, motility, phosphorylation of HER receptors and downstream signalling is achieved via reduced shedding of ADAM17 ligands. These findings underscore the importance of ADAM17 and suggest that D1(A12) might be an effective targeted agent for treating EGFR TKI-resistant HNSCC.
authors.affiliation: 1. Cancer Research UK Cambridge Institute, University of Cambridge, Department of Oncology, UK ; 2. IONTAS Ltd, Hopkins Building, Tennis Court Rd., Cambridge CB2 1QW, UK (current address).
authors.forename: Yanchao
authors.initials: Y
authors.lastname: Huang
authors.affiliation: 1. Cancer Research UK Cambridge Institute, University of Cambridge, Department of Oncology, UK ; 4. Centre for Stem Cells and Regenerative Medicine, King's College London School of Medicine, 28th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK (current address).
authors.forename: Nathan
authors.initials: N
authors.lastname: Benaich
authors.affiliation: 1. Cancer Research UK Cambridge Institute, University of Cambridge, Department of Oncology, UK ; 5. The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK (current address).
authors.forename: Christopher
authors.initials: C
authors.lastname: Tape
authors.affiliation: 1. Cancer Research UK Cambridge Institute, University of Cambridge, Department of Oncology, UK ; 3. Faculty of Health Sciences, University of Macau, Macau (current address).
authors.forename: Hang Fai
authors.initials: HF
authors.lastname: Kwok
authors.affiliation: 1. Cancer Research UK Cambridge Institute, University of Cambridge, Department of Oncology, UK.
authors.forename: Gillian
authors.initials: G
authors.lastname: Murphy
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000906:Antibodies / Q000494:pharmacology / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000378:metabolism; D000077156:Gefitinib; D055785:Gene Knockdown Techniques; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D000906:Antibodies; D008565:Membrane Proteins; D011799:Quinazolines; D066246:ErbB Receptors; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; D000077156:Gefitinib
keywords: ADAM17; HER receptor and ligands; cell proliferation and motility.; inhibitory antibody