title: Secretome Signature Identifies ADAM17 as Novel Target for Radiosensitization of Non-Small Cell Lung Cancer.
abstract: OBJECTIVE
  Ionizing radiation (IR) induces intracellular signaling processes as part of a treatment-induced stress response. Here we investigate IR-induced ADAM17 activation and the role of ADAM17-shed factors for radiation resistance in non-small cell lung cancer.
  
  
  METHODS
  Large-scale secretome profiling was performed using antibody arrays. Secretion kinetics of ADAM17 substrates was determined using ELISA across multiple in vitro and in vivo models of non-small cell lung cancer. Clonogenic survival and tumor xenograft assays were performed to determine radiosensitization by ADAM17 inhibition.
  
  
  RESULTS
  On the basis of a large-scale secretome screening, we investigated secretion of auto- or paracrine factors in non-small cell lung cancer in response to irradiation and discovered the ADAM17 network as a crucial mediator of resistance to IR. Irradiation induced a dose-dependent increase of furin-mediated cleavage of the ADAM17 proform to active ADAM17, which resulted in enhanced ADAM17 activity in vitro and in vivo Genetic or pharmacologic targeting of ADAM17 suppressed IR-induced shedding of secreted factors, downregulated ErbB signaling in otherwise cetuximab-resistant target cells, and enhanced IR-induced cytotoxicity. The combined treatment modality of IR with the ADAM17 inhibitor TMI-005 resulted in a supra-additive antitumor response in vivo demonstrating the potential of ADAM17 targeting in combination with radiotherapy.
  
  
  CONCLUSIONS
  Radiotherapy activates ADAM17 in non-small cell lung cancer, which results in shedding of multiple survival factors, growth factor pathway activation, and IR-induced treatment resistance. We provide a sound rationale for repositioning ADAM17 inhibitors as short-term adjuvants to improve the radiotherapy outcome of non-small cell lung cancer. Clin Cancer Res; 22(17); 4428-39. ©2016 AACR.
authors.affiliation: Laboratory for Applied Radiobiology, Department of Radiation Oncology, University Hospital Zurich, University of Zurich Zurich, Switzerland.
authors.forename: Ashish
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Laboratory for Applied Radiobiology, Department of Radiation Oncology, University Hospital Zurich, University of Zurich Zurich, Switzerland.
authors.forename: Sabine
authors.initials: S
authors.lastname: Bender
authors.affiliation: Laboratory for Applied Radiobiology, Department of Radiation Oncology, University Hospital Zurich, University of Zurich Zurich, Switzerland.
authors.forename: Martina
authors.initials: M
authors.lastname: Zimmermann
authors.affiliation: Laboratory for Applied Radiobiology, Department of Radiation Oncology, University Hospital Zurich, University of Zurich Zurich, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Riesterer
authors.affiliation: Laboratory for Applied Radiobiology, Department of Radiation Oncology, University Hospital Zurich, University of Zurich Zurich, Switzerland.
authors.forename: Angela
authors.initials: A
authors.lastname: Broggini-Tenzer
authors.affiliation: Laboratory for Applied Radiobiology, Department of Radiation Oncology, University Hospital Zurich, University of Zurich Zurich, Switzerland. martin.pruschy@usz.ch.
authors.forename: Martin N
authors.initials: MN
authors.lastname: Pruschy
mesh_terms: D000072198:ADAM17 Protein / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D014408:Biomarkers, Tumor; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D045744:Cell Line, Tumor; D002470:Cell Survival; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000528:radiation effects; D045683:Furin / Q000378:metabolism; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D051379:Mice; D011499:Protein Processing, Post-Translational / Q000528:radiation effects; D020543:Proteome; D040901:Proteomics / Q000379:methods; D034622:RNA Interference; D011836:Radiation Tolerance / Q000235:genetics; D011839:Radiation, Ionizing; D015398:Signal Transduction / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D020543:Proteome; D045683:Furin; D000072198:ADAM17 Protein