LUBAC determines chemotherapy resistance in squamous cell lung cancer
E Josue Ruiz
Markus E Diefenbacher
Jessica K Nelson
Rocio Sancho
Fabio Pucci
Atanu Chakraborty
Paula Moreno
Alessandro Annibaldi
Gianmaria Liccardi
Vesela Encheva
Richard Mitter
Mathias Rosenfeldt
Ambrosius P Snijders
Pascal Meier
Marco A Calzado
Axel Behrens
10779/crick.11409657.v1
https://crick.figshare.com/articles/journal_contribution/LUBAC_determines_chemotherapy_resistance_in_squamous_cell_lung_cancer/11409657
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.
2019-12-19 18:08:01
Adenocarcinoma of Lung
Animals
Carcinoma, Squamous Cell
Cisplatin
Drug Resistance, Neoplasm
Humans
Lung Neoplasms
Mice
Multienzyme Complexes
Proto-Oncogene Proteins p21(ras)
Ubiquitination
Behrens FC001039
PRT
CB
BRF-ack
GEP-ack
HP-ack
11 Medical and Health Sciences
Immunology