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ADAM17 selectively activates the IL-6 trans-signaling/ERK MAPK axis in KRAS-addicted lung cancer.
- Source :
-
EMBO molecular medicine [EMBO Mol Med] 2019 Apr; Vol. 11 (4). - Publication Year :
- 2019
-
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 <superscript>G12D</superscript> -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 <superscript>G12D</superscript> -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.<br /> (© 2019 The Authors. Published under the terms of the CC BY 4.0 license.)
- Subjects :
- ADAM17 Protein antagonists & inhibitors
Animals
Cell Line, Tumor
Genotype
Humans
Lung Neoplasms pathology
Mice
Mitogen-Activated Protein Kinase 1 metabolism
Mitogen-Activated Protein Kinase 3 metabolism
Mutation
Phosphorylation
Signal Transduction
p38 Mitogen-Activated Protein Kinases metabolism
ADAM17 Protein metabolism
Proto-Oncogene Proteins p21(ras) genetics
Receptors, Interleukin-6 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1757-4684
- Volume :
- 11
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- EMBO molecular medicine
- Publication Type :
- Academic Journal
- Accession number :
- 30833304
- Full Text :
- https://doi.org/10.15252/emmm.201809976