ADAM17 and Ionizing Radiation in NSCLC

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:Based on 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 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.

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