방사선의학 웹진

바로가기  >

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.​ 

Translational Relevance

Intrinsic and acquired resistances to ionizing radiation (IR) represent a major challenge in the treatment of NSCLC. A recent phase III trial for patients with stage IIIA or IIIB NSCLC (RTOG 0617) demonstrated that addition of the EGFR-directed mAb cetuximab to concurrent chemoradiation and consolidation treatment did not provide any added benefit. Thus, novel molecular targets for anticancer agents alone and in combination with radiotherapy are of high demand. The sheddase ADAM17 is associated with aggressive progression and poor prognosis in NSCLC and activates multiple ErbB- and non-ErbB–related pathways. Here we demonstrate that genetic and pharmacologic inhibition of ADAM17 sensitizes in vitro and in vivo NSCLC to IR. The findings of this study suggest that clinically relevant ADAM17 inhibitors should be considered for the treatment of NSCLC in combination with radiotherapy.​ 

Author information​

Sharma A1, Bender S1, Zimmermann M1, Riesterer O1, Broggini-Tenzer A1, Pruschy MN2.

1Laboratory for Applied Radiobiology, Department of Radiation Oncology, University Hospital Zurich, University of Zurich Zurich, Switzerland.

2Laboratory for Applied Radiobiology, Department of Radiation Oncology, University Hospital Zurich, University of Zurich Zurich, Switzerland. martin.pruschy@usz.ch.