Pharmacological inhibition of ADAM17 with the small molecular inhibitor TMI-005 or siRNA-based targeting of ADAM17 suppressed RT-induced shedding of these factors, downregulated ErbB1-signaling in target cells and enhanced RT-induced cytotoxicity in vitro and in vivo (tumor xenograft model) even in tumors resistant to ErbB-targeting cancer therapeutics. Here, ADAM17 is linked to cancer.