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EMBO Mol Med. 2019 Apr;11(4). pii: e9976. doi: 10.15252/emmm.201809976.

ADAM17 selectively activates the IL-6 trans-signaling/ERK MAPK axis in KRAS-addicted lung cancer.

Author information

1
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Vic., Australia.
2
Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Vic., Australia.
3
Cancer Program, Monash Biomedicine Discovery Institute, Clayton, Vic., Australia.
4
Department of Anatomy and Developmental Biology, Monash University, Clayton, Vic., Australia.
5
Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Vic., Australia.
6
Department of Surgery, School of Clinical Sciences at Monash Health, Monash University, Clayton, Vic., Australia.
7
Department of Cardiothoracic Surgery, Monash Health, Clayton, Vic., Australia.
8
Monash Biobank, Monash Health, Clayton, Vic., Australia.
9
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
10
School of Health and Biomedical Sciences, RMIT University, Bundoora, Vic., Australia.
11
Genetics and Molecular Pathology Laboratory, Monash Health, Clayton, Vic., Australia.
12
Department of Human Genetics, Tokushima University Graduate School of Medicine, Tokushima, Japan.
13
Division of Molecular Genetics, Aichi Cancer Center Research Institute, Nagoya, Japan.
14
Division of Molecular Therapeutics, Aichi Cancer Center Research Institute, Nagoya, Japan.
15
Division of Advanced Cancer Therapeutics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
16
NovImmune SA, Geneva, Switzerland.
17
Department of Pathology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
18
Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
19
Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany.
20
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Vic., Australia brendan.jenkins@hudson.org.au.

Abstract

Oncogenic KRAS mutations are major drivers of lung adenocarcinoma (LAC), yet the direct therapeutic targeting of KRAS has been problematic. Here, we reveal an obligate requirement by oncogenic KRAS for the ADAM17 protease in LAC In genetically engineered and xenograft (human cell line and patient-derived) Kras G12D-driven LAC models, the specific blockade of ADAM17, including with a non-toxic prodomain inhibitor, suppressed tumor burden by reducing cellular proliferation. The pro-tumorigenic activity of ADAM17 was dependent upon its threonine phosphorylation by p38 MAPK, along with the preferential shedding of the ADAM17 substrate, IL-6R, to release soluble IL-6R that drives IL-6 trans-signaling via the ERK1/2 MAPK pathway. The requirement for ADAM17 in Kras G12D-driven LAC was independent of bone marrow-derived immune cells. Furthermore, in KRAS mutant human LAC, there was a significant positive correlation between augmented phospho-ADAM17 levels, observed primarily in epithelial rather than immune cells, and activation of ERK and p38 MAPK pathways. Collectively, these findings identify ADAM17 as a druggable target for oncogenic KRAS-driven LAC and provide the rationale to employ ADAM17-based therapeutic strategies for targeting KRAS mutant cancers.

KEYWORDS:

ERK MAPK ; KRAS ; ADAM17; IL‐6 trans‐signaling; lung adenocarcinoma

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