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LUBAC determines chemotherapy resistance in squamous cell lung cancer

E Josue Ruiz1, Markus E Diefenbacher1, Jessica K Nelson1

  • 1Adult Stem Cell Laboratory, The Francis Crick Institute, London, UK.

The Journal of Experimental Medicine
|January 16, 2019
PubMed

Insights

FBW7 inactivation drives lung cancer, with CC10+ cells originating squamous cell carcinoma. LUBAC-NF-κB signaling confers cisplatin resistance, offering a new therapeutic target for lung squamous cell carcinoma patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Lung squamous cell carcinoma (LSCC) and lung adenocarcinoma (LADC) are major lung cancer subtypes.
  • Targeted therapies benefit LADC patients but show limited efficacy in LSCC.
  • The tumor suppressor FBW7 is frequently altered in human LSCC.

Purpose of the Study:

  • To investigate the role of FBW7 inactivation in lung cancer development.
  • To identify the cell of origin for LSCC in a mouse model.
  • To elucidate mechanisms of chemotherapy resistance in LSCC.

Main Methods:

  • Utilized a mouse model with oncogenic KRasG12D and Fbxw7 inactivation (KF model).
  • Employed lineage-tracing experiments to identify LSCC cell origins.
  • Analyzed LUBAC-mediated NF-κB signaling in human and mouse LSCC.

Main Results:

  • The KF model developed both LSCC and LADC.
  • CC10+ cells, not basal cells, were identified as the origin of LSCC.
  • LSCC tumors exhibited resistance to cisplatin, linked to LUBAC-NF-κB signaling.
  • Inhibiting NF-κB activation resensitized tumors to cisplatin.

Conclusions:

  • FBW7 inactivation is a key driver of LSCC and LADC.
  • CC10+ cells are the progenitor cells for LSCC.
  • LUBAC-mediated NF-κB signaling is crucial for LSCC chemoresistance.
  • Targeting NF-κB signaling presents a promising therapeutic strategy for LSCC.

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