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

Mohamed I Saad1,2, Sultan Alhayyani1,2, Louise McLeod1,2

  • 1Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Vic., Australia.

EMBO Molecular Medicine
|March 6, 2019
PubMed

Insights

Targeting ADAM17 protease is a promising strategy for KRAS-mutant lung adenocarcinoma. Blocking ADAM17 reduces tumor growth by inhibiting proliferation and IL-6 trans-signaling pathways.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Oncogenic KRAS mutations are key drivers of lung adenocarcinoma (LAC).
  • Directly targeting KRAS has proven challenging, necessitating alternative therapeutic strategies.
  • ADAM17 protease has emerged as a potential mediator in KRAS-driven cancers.

Purpose of the Study:

  • To investigate the role of ADAM17 protease in KRAS-driven lung adenocarcinoma.
  • To determine if ADAM17 is a druggable target for treating KRAS-mutant LAC.
  • To elucidate the molecular mechanisms by which ADAM17 promotes tumor growth.

Main Methods:

  • Utilized genetically engineered and xenograft models of KRAS G12D-driven LAC.
  • Employed a non-toxic prodomain inhibitor to block ADAM17 activity.
  • Assessed tumor burden, cellular proliferation, and MAPK signaling pathways (p38, ERK).
  • Investigated the role of ADAM17 substrate IL-6R and IL-6 trans-signaling.
  • Analyzed phospho-ADAM17 levels in human KRAS-mutant LAC samples.

Main Results:

  • Specific blockade of ADAM17 significantly suppressed tumor burden and reduced cellular proliferation in KRAS G12D-driven LAC models.
  • ADAM17's pro-tumorigenic activity was dependent on p38 MAPK-mediated threonine phosphorylation.
  • ADAM17 shedding of IL-6R released soluble IL-6R, driving IL-6 trans-signaling via ERK1/2 MAPK.
  • The requirement for ADAM17 was independent of bone marrow-derived immune cells.
  • Human KRAS-mutant LAC showed a positive correlation between phospho-ADAM17 levels and activated ERK/p38 MAPK pathways.

Conclusions:

  • ADAM17 is an obligate requirement for oncogenic KRAS-driven lung adenocarcinoma.
  • ADAM17 is a druggable target for therapeutic intervention in KRAS-mutant LAC.
  • Targeting ADAM17 offers a promising strategy for treating KRAS-driven cancers.
Keywords:
ERK MAPKKRASADAM17IL‐6 trans‐signalinglung adenocarcinoma

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