Secretome Signature Identifies ADAM17 as Novel Target for Radiosensitization of Non–Small Cell Lung Cancer

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 IRinduced 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. Ó2016 AACR.

CXCR4 Accelerates Osteoclastogenesis Induced by Non-Small Cell Lung Carcinoma Cells Through Self-Potentiation and VCAM1 Secretion

“…Aberrant ADAM17 expression was associated with a poor survival time [39]. ADAM17 can be activated by radiotherapy in NSCLC, which results in shedding of multiple survival factors and growth factor pathway activation [40]. A previous study showed that ADAM17 downregulation suppresses NSCLC migration and invasion [38].…”

ADAM 17 selectively activates the IL ‐6 trans‐signaling/ ERK MAPK axis in KRAS ‐addicted lung cancer

“…In light of the promising preclinical activity of A17pro in the oncogenic setting of KRAS mutant LAC, we note that previous studies based on the use of non‐specific SMIs (e.g., hydroxamates) or RNA interference‐based approaches (siRNA, shRNA) in NSCLC cell lines have suggested that ADAM17 may have anti‐cancer activity in lung cancer (Zhou et al , ; Baumgart et al , ; Lv et al , ; Sharma et al , ). However, in contrast to our current study, the clinical utility of ADAM17 specifically in mutant KRAS LAC (which accounts for ~15% of all lung cancers) was not investigated.…”

“…The limited number of studies investigating ADAM17 in NSCLC has suggested that elevated ADAM17 expression correlates with numerous clinicopathological characteristics (e.g., tumor grade) and poor survival (Ni et al , ). Furthermore , in human NSCLC cell lines, ADAM17 can modulate EGFR signaling either indirectly via Notch1 shedding and activation leading to increased EGFR expression, or directly via shedding of EGFR family ligands, the latter of which may contribute to radiotherapy resistance of NSCLC tumors (Zhou et al , ; Baumgart et al , ; Sharma et al , ). However, the role of ADAM17 in the predominant LAC subtype and its association with KRAS mutation status, as well as the involvement of other ADAM17 substrates in LAC, are unknown.…”

Savior or not: ADAM17 inhibitors overcome radiotherapy-resistance in non-small cell lung cancer

“…Nor did they check whether proteinase activity of ADAM17 is required for the acquisition of IR therapy resistance. Expression of not all ADAM17-cleaved substrates including HB-EGF were increased by irradiation in the paper, and they did not figure out these points (7). Collectively, precise mechanisms of ADAM17-mediated IR therapy resistance still remain to be elucidated by further analysis.…”

“…Pretreatment with anti-ADAM17 siRNAs or a metalloproteinase inhibitor, TMICommentary Savior or not: ADAM17 inhibitors overcome radiotherapyresistance in non-small cell lung cancer 005 (apratastat), in A549 cells sensitized them to IR and downregulated phosphorylation levels of EGFR. Moreover, a combination of anti-ADAM17 reagents (anti-ADAM17 siRNA or TMI-005) with IR therapy prolonged survival compared with mice taking Cetuximab and IR therapy (7).…”