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

Mohamed I. Saad, Sultan Alhayyani, Louise McLeod, Liang Yu, Mohammad Alanazi, Virginie Deswaerte, Ke Tang, Thierry Jarde, Julian A Smith, Zdenka Prodanovic, Michelle D Tate, Jesse J Balic, D Neil Watkins, Jason E Cain, Steven Bozinovski, Elizabeth Algar, Tomohiro Kohmoto, Hiromichi Ebi, Walter Ferlin, Christoph Garbers & 4 others Saleela Ruwanpura, Irit Sagi, Stefan Rose-John, Brendan J Jenkins

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Article numbere9976
Number of pages19
JournalEMBO Molecular Medicine
Volume11
Issue number4
DOIs
Publication statusPublished - Apr 2019

Keywords

  • ADAM17
  • ERK MAPK
  • IL-6 trans-signaling
  • KRAS
  • lung adenocarcinoma

Cite this

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. / ADAM17 selectively activates the IL-6 trans-signaling/ERK MAPK axis in KRAS-addicted lung cancer. In: EMBO Molecular Medicine. 2019 ; Vol. 11, No. 4.
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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 = "ADAM17, ERK MAPK, IL-6 trans-signaling, KRAS, lung adenocarcinoma",
author = "Saad, {Mohamed I.} and Sultan Alhayyani and Louise McLeod and Liang Yu and Mohammad Alanazi and Virginie Deswaerte and Ke Tang and Thierry Jarde and Smith, {Julian A} and Zdenka Prodanovic and Tate, {Michelle D} and Balic, {Jesse J} and Watkins, {D Neil} and Cain, {Jason E} and Steven Bozinovski and Elizabeth Algar and Tomohiro Kohmoto and Hiromichi Ebi and Walter Ferlin and Christoph Garbers and Saleela Ruwanpura and Irit Sagi and Stefan Rose-John and Jenkins, {Brendan J}",
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language = "English",
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Saad, MI, Alhayyani, S, McLeod, L, Yu, L, Alanazi, M, Deswaerte, V, Tang, K, Jarde, T, Smith, JA, Prodanovic, Z, Tate, MD, Balic, JJ, Watkins, DN, Cain, JE, Bozinovski, S, Algar, E, Kohmoto, T, Ebi, H, Ferlin, W, Garbers, C, Ruwanpura, S, Sagi, I, Rose-John, S & Jenkins, BJ 2019, 'ADAM17 selectively activates the IL-6 trans-signaling/ERK MAPK axis in KRAS-addicted lung cancer' EMBO Molecular Medicine, vol. 11, no. 4, e9976. https://doi.org/10.15252/emmm.201809976

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

In: EMBO Molecular Medicine, Vol. 11, No. 4, e9976, 04.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - ADAM17 selectively activates the IL-6 trans-signaling/ERK MAPK axis in KRAS-addicted lung cancer

AU - Saad, Mohamed I.

AU - Alhayyani, Sultan

AU - McLeod, Louise

AU - Yu, Liang

AU - Alanazi, Mohammad

AU - Deswaerte, Virginie

AU - Tang, Ke

AU - Jarde, Thierry

AU - Smith, Julian A

AU - Prodanovic, Zdenka

AU - Tate, Michelle D

AU - Balic, Jesse J

AU - Watkins, D Neil

AU - Cain, Jason E

AU - Bozinovski, Steven

AU - Algar, Elizabeth

AU - Kohmoto, Tomohiro

AU - Ebi, Hiromichi

AU - Ferlin, Walter

AU - Garbers, Christoph

AU - Ruwanpura, Saleela

AU - Sagi, Irit

AU - Rose-John, Stefan

AU - Jenkins, Brendan J

PY - 2019/4

Y1 - 2019/4

N2 - 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.

AB - 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.

KW - ADAM17

KW - ERK MAPK

KW - IL-6 trans-signaling

KW - KRAS

KW - lung adenocarcinoma

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