Oncogenic KRAS mutations are a major driver of lung cancer. Considering the direct therapeutic targeting of KRAS has been problematic, the identification of “druggable” cooperating factors of KRAS provides an attractive approach to develop new strategies that indirectly block the actions of KRAS. Since a disintegrin and metalloproteinase 17 (ADAM17) is responsible for the ectodomain shedding of bioactive protumourigenic interleukins, growth factors and/or their receptors implicated in lung cancer, including TNFα, soluble IL-6 receptor (sIL-6R), and EGF receptor ligands, we investigated the role of ADAM17 in the pathogenesis of lung cancer.
Genetic (KrasLSL-G12D/+) and carcinogen (NNK)-induced mouse models of lung adenocarcinoma (LAC) were coupled with Adam17ex/ex mice, which are homozygous for a hypomorphic Adam17 allele resulting in a dramatic reduction in ADAM17 expression. Oncogenic KrasG12D was activated using intranasal inhalation of Adenovirus Cre recombinase, while NNK (100mg/kg) was injected into Adam17ex/ex on A/J background. CRISPR-Cas9-mediated knockdown of ADAM17 in human KRAS-mutant LAC cell lines was employed to evaluate the effects of ADAM17 deletion in-vitro and in-vivo (xenograft). The in-vivo anti-tumour activity of the recombinant ADAM17 prodomain (A17pro), which is a highly-specific inhibitor of ADAM17 activity, was evaluated in KrasG12D-driven LAC and KRAS-mutant LAC patient-derived xenograft (PDX) models.
Genetic deficiency of ADAM17 significantly reduced tumour burden in both KrasG12D and NNK-induced LAC models, which was accompanied by reduced cellular proliferation. CRISPR-Cas9-driven ADAM17 deficiency in KRAS-mutant cell lines similarly reduced cell proliferation and tumour growth in-vitro and in-vivo, respectively. Furthermore, A17pro treatment significantly reduced tumour burden in KrasG12D mice, as well as tumour growth of KRAS-mutant PDX. Only sIL-6R was preferentially reduced in LAC mouse models upon the targeted blockade of ADAM17 expression/activity, which was associated with a concomitant reduction in ERK1/2 MAPK activation.
Our data suggest that ADAM17 plays a pivotal role in LAC development. Moreover, targeting ADAM17 activity using the A17pro inhibitor represents an attractive strategy in tacking LAC.