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

• Published in: EMBO molecular medicine 2019-04, Vol.11 (4), p.1-n/a
• Main Authors: Saad, Mohamed I, Alhayyani, Sultan, McLeod, Louise, Yu, Liang, Alanazi, Mohammad, Deswaerte, Virginie, Tang, Ke, Jarde, Thierry, Smith, Julian A, Prodanovic, Zdenka, Tate, Michelle D, Balic, Jesse J, Watkins, D Neil, Cain, Jason E, Bozinovski, Steven, Algar, Elizabeth, Kohmoto, Tomohiro, Ebi, Hiromichi, Ferlin, Walter, Garbers, Christoph, Ruwanpura, Saleela, Sagi, Irit, Rose‐John, Stefan, Jenkins, Brendan J
• Format: Article
• Language: English
• Subjects: ADAM17; ADAM17 Protein - antagonists & inhibitors; ADAM17 Protein - metabolism; Animals; Cell Line, Tumor; EMBO03; EMBO35; ERK MAPK; Genotype; Humans; IL‐6 trans‐signaling; KRAS; lung adenocarcinoma; Lung Neoplasms - pathology; Mice; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Mutation; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation; Proto-Oncogene Proteins p21(ras) - genetics; Receptors, Interleukin-6 - metabolism; Research Article; Signal Transduction
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.201809976

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. Synopsis Oncogenic KRAS mutations are associated with one‐third of lung adenocarcinoma (LAC) cases, yet the downstream molecular events that facilitate KRAS‐mediated tumorigenesis in the lung remain unresolved. This study reveals an obligate requirement by oncogenic KRAS for the ADAM17 protease in LAC. The specific genetic and therapeutic targeting of ADAM17, the latter with a non‐toxic prodomain inhibitor, suppressed tumour burden by reducing cellular proliferation in genetically‐engineered and xenograft mutant KRAS‐driven LAC models. The pro‐tumorigenic activity of ADAM17 in LAC was dependent upon its threonine phosphorylation by p38 MAPK. ADAM17 preferentially shed the substrate, IL‐6R, during LAC to release soluble IL‐6R that drives IL‐6 trans‐signaling via the ERK1/2 MAPK pathway. The requirement for ADAM17 in mutant KRAS‐driven LAC was independent of bone marrow‐derived hematopoietic immune cells. In KRAS mutant human LAC, augmented phospho‐ADAM17 levels were observed primarily in epithelial rather than immune cells, and significantly and positively correlated with activated p38 and ERK1/2 MAPK pathways. Graphical Abstract Oncogenic KRAS mutations are associated with one‐third of lung adenocarcinoma