LUBAC determines chemotherapy resistance in squamous cell lung cancer
LUBAC determines chemotherapy resistance in squamous cell lung cancer
Lung squamous cell carcinoma (LSCC) and adenocarcinoma (LADC) are the most common lung cancer subtypes. Molecular targeted treatments have improved LADC patient survival but are largely ineffective in LSCC. The tumor suppressor FBW7 is commonly mutated or down-regulated in human LSCC, and oncogenic KRasG12D activation combined with Fbxw7 inactivation in mice (KF model) caused both LSCC and LADC. Lineage-tracing experiments showed that CC10+, but not basal, cells are the cells of origin of LSCC in KF mice. KF LSCC tumors recapitulated human LSCC resistance to cisplatin-based chemotherapy, and we identified LUBAC-mediated NF-κB signaling as a determinant of chemotherapy resistance in human and mouse. Inhibition of NF-κB activation using TAK1 or LUBAC inhibitors resensitized LSCC tumors to cisplatin, suggesting a future avenue for LSCC patient treatment.
Adenocarcinoma of Lung/drug therapy, Animals, Carcinoma, Squamous Cell/drug therapy, Cisplatin/pharmacology, Drug Resistance, Neoplasm, Humans, Lung Neoplasms/drug therapy, Mice, Multienzyme Complexes/genetics, Proto-Oncogene Proteins p21(ras)/genetics, Ubiquitination
450-465
Ruiz, E. Josue
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Diefenbacher, Markus E.
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Nelson, Jessica K.
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Sancho, Rocio
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Pucci, Fabio
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Chakraborty, Atanu
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Moreno, Paula
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Annibaldi, Alessandro
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Liccardi, Gianmaria
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Encheva, Vesela
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Mitter, Richard
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Rosenfeldt, Mathias
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Snijders, Ambrosius P
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Meier, Pascal
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Calzado, Marco A.
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Behrens, Axel
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14 January 2019
Ruiz, E. Josue
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Diefenbacher, Markus E.
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Nelson, Jessica K.
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Sancho, Rocio
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Pucci, Fabio
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Chakraborty, Atanu
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Moreno, Paula
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Annibaldi, Alessandro
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Liccardi, Gianmaria
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Encheva, Vesela
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Mitter, Richard
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Rosenfeldt, Mathias
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Snijders, Ambrosius P
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Meier, Pascal
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Calzado, Marco A.
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Behrens, Axel
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Ruiz, E. Josue, Diefenbacher, Markus E., Nelson, Jessica K., Sancho, Rocio, Pucci, Fabio, Chakraborty, Atanu, Moreno, Paula, Annibaldi, Alessandro, Liccardi, Gianmaria, Encheva, Vesela, Mitter, Richard, Rosenfeldt, Mathias, Snijders, Ambrosius P, Meier, Pascal, Calzado, Marco A. and Behrens, Axel
(2019)
LUBAC determines chemotherapy resistance in squamous cell lung cancer.
The Journal of Experimental Medicine, 216 (2), .
(doi:10.1084/jem.20180742).
Abstract
Lung squamous cell carcinoma (LSCC) and adenocarcinoma (LADC) are the most common lung cancer subtypes. Molecular targeted treatments have improved LADC patient survival but are largely ineffective in LSCC. The tumor suppressor FBW7 is commonly mutated or down-regulated in human LSCC, and oncogenic KRasG12D activation combined with Fbxw7 inactivation in mice (KF model) caused both LSCC and LADC. Lineage-tracing experiments showed that CC10+, but not basal, cells are the cells of origin of LSCC in KF mice. KF LSCC tumors recapitulated human LSCC resistance to cisplatin-based chemotherapy, and we identified LUBAC-mediated NF-κB signaling as a determinant of chemotherapy resistance in human and mouse. Inhibition of NF-κB activation using TAK1 or LUBAC inhibitors resensitized LSCC tumors to cisplatin, suggesting a future avenue for LSCC patient treatment.
Text
jem_20180742
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Accepted/In Press date: 20 December 2018
Published date: 14 January 2019
Keywords:
Adenocarcinoma of Lung/drug therapy, Animals, Carcinoma, Squamous Cell/drug therapy, Cisplatin/pharmacology, Drug Resistance, Neoplasm, Humans, Lung Neoplasms/drug therapy, Mice, Multienzyme Complexes/genetics, Proto-Oncogene Proteins p21(ras)/genetics, Ubiquitination
Identifiers
Local EPrints ID: 505339
URI: http://eprints.soton.ac.uk/id/eprint/505339
ISSN: 0022-1007
PURE UUID: 5d4afa70-41ae-41ac-ae41-0c6b15d122f5
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Date deposited: 07 Oct 2025 16:37
Last modified: 08 Oct 2025 02:17
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Contributors
Author:
E. Josue Ruiz
Author:
Markus E. Diefenbacher
Author:
Jessica K. Nelson
Author:
Rocio Sancho
Author:
Fabio Pucci
Author:
Atanu Chakraborty
Author:
Paula Moreno
Author:
Alessandro Annibaldi
Author:
Gianmaria Liccardi
Author:
Vesela Encheva
Author:
Richard Mitter
Author:
Mathias Rosenfeldt
Author:
Ambrosius P Snijders
Author:
Pascal Meier
Author:
Marco A. Calzado
Author:
Axel Behrens
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