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

Saad, M, Alhayyani, S, McLeod, L and Bozinovski, S et al., 2019, 'ADAM17 selectively activates the IL-6 trans-signaling/ERK MAPK axis in KRAS-addicted lung cancer', EMBO Molecular Medicine, vol. 11, no. 4, pp. 1-19.


Document type: Journal Article
Collection: Journal Articles

Title ADAM17 selectively activates the IL-6 trans-signaling/ERK MAPK axis in KRAS-addicted lung cancer
Author(s) Saad, M
Alhayyani, S
McLeod, L
Bozinovski, S et al.,
Year 2019
Journal name EMBO Molecular Medicine
Volume number 11
Issue number 4
Start page 1
End page 19
Total pages 19
Publisher Wiley-Blackwell Publishing
Abstract Published under the terms of the CC BY 4.0 license 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.
Subject Respiratory Diseases
Keyword(s) ADAM17
ERK MAPK
IL-6 trans-signaling
KRAS
lung adenocarcinoma
DOI - identifier 10.15252/emmm.201809976
Copyright notice © 2019 The Authors
ISSN 1757-4676
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