LUBAC determines chemotherapy resistance in squamous cell lung cancer.

E Josue Ruiz,Atanu Chakraborty,Rocio Sancho,Vesela Encheva,Mathias Rosenfeldt,Ambrosius P Snijders,Pascal Meier,Gianmaria Liccardi,Axel Behrens,Fabio Pucci,Richard Mitter,Jessica K Nelson,Markus E Diefenbacher,Paula Moreno,Alessandro Annibaldi,Marco A Calzado

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.

Highlights

Lung cancer is the most common epithelial tumor and the leading cause of cancer death worldwide
These data suggest that F-box/WD repeat-containing protein 7 (FBW7) is lost or down-regulated frequently in human Lung squamous cell carcinoma (LSCC), and that FBW7 inactivation could be a driver of human LSCC
KRAS mutations are very frequently observed in human lung adenocarcinoma (LADC), but the RAS tumor driver pathway is activated in up to half of human LSCC tumors, most commonly due to transcriptional up-regulation and amplification of KRAS and the upstream receptor tyrosine kinases epidermal growth factor receptor (EGFR) and FGFR1 (Fig. S1 A; Cancer Genome Atlas Research Network, 2012; Campbell et al, 2016)

Summary

Introduction

Lung cancer is the most common epithelial tumor and the leading cause of cancer death worldwide It is histologically differentiated into small cell lung cancer (SCLC) and non– small cell lung cancer (NSCLC). Progress has been made in the targeted treatment of LADC, largely due to the development of small-molecule inhibitors against epidermal growth factor receptor (EGFR), anaplastic lymphoma receptor tyrosine kinase (ALK), and ROS1 (Cardarella and Johnson, 2013). Such treatments have proved ineffective for LSCC patients (Novello et al, 2014; Hirsch et al, 2017). Elucidating the critical molecular pathways involved in LSCC is crucial to identify new therapeutic approaches

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