LUBAC determines chemotherapy resistance in squamous cell lung cancer.
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Date
2019-02-04Author
Ruiz, EJ
Diefenbacher, ME
Nelson, JK
Sancho, R
Pucci, F
Chakraborty, A
Moreno, P
Annibaldi, A
Liccardi, G
Encheva, V
Mitter, R
Rosenfeldt, M
Snijders, AP
Meier, P
Calzado, MA
Behrens, A
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Animals
Humans
Mice
Carcinoma, Squamous Cell
Lung Neoplasms
Cisplatin
Multienzyme Complexes
Drug Resistance, Neoplasm
Proto-Oncogene Proteins p21(ras)
Ubiquitination
Adenocarcinoma of Lung
Language
eng
Date accepted
2018-12-18
License start date
2019-02
Citation
The Journal of experimental medicine, 2019, 216 (2), pp. 450 - 465
Publisher
ROCKEFELLER UNIV PRESS