Lymphotoxin-beta interacts with methylated EGFR to mediate acquired resistance to cetuximab in head and neck cancer

Hsu, D.S., Hwang, W.L., Yuh, C.H., Chu, C.H., Ho, Y.H., Chen, P.B., Lin, H.S., Lin, H.K., Wu, S.P., Lin, C.Y., Hsu, W.H., Lan, H.Y., Wang, H.J., Tai, S.K., Hung, M.C., Yang, M.H.
Clinical cancer research : an official journal of the American Association for Cancer Research   23(15): 4388-4401 (Journal)
Registered Authors
Lin, Han-Syuan, Yuh, Chiou-Hwa (Cathy)
MeSH Terms
  • Animals
  • Carcinoma, Squamous Cell/drug therapy*
  • Carcinoma, Squamous Cell/genetics
  • Carcinoma, Squamous Cell/pathology
  • Cell Line, Tumor
  • Cetuximab/administration & dosage
  • Cetuximab/adverse effects
  • Disease Models, Animal
  • Drug Resistance, Neoplasm/genetics
  • Epithelial-Mesenchymal Transition/drug effects
  • Epithelial-Mesenchymal Transition/genetics*
  • Head and Neck Neoplasms/drug therapy*
  • Head and Neck Neoplasms/genetics
  • Head and Neck Neoplasms/pathology
  • Humans
  • Lymphotoxin-beta/genetics*
  • Mice
  • Mutation
  • NF-kappa B/antagonists & inhibitors*
  • NF-kappa B/genetics
  • Protein Kinase Inhibitors/administration & dosage
  • Protein Kinase Inhibitors/adverse effects
  • Protein-Arginine N-Methyltransferases/genetics
  • Repressor Proteins/genetics
  • Snail Family Transcription Factors/genetics
  • Xenograft Model Antitumor Assays
  • Zebrafish
  • Zebrafish Proteins/genetics
28196873 Full text @ Clin. Cancer Res.
Purpose: In head and neck squamous cell carcinoma (HNSCC), the incidence of RAS mutation, which is the major cause of cetuximab resistance, is relatively rare compared with the other types of cancers, and the mechanism mediating acquired resistance is unclear compared with the driver gene mutation-mediated de novo resistance. Here, we investigated the driver gene mutation-independent mechanism for cetuximab resistance in HNSCC.Experimental Design: We used the in vitro-selected and in vivo-selected cetuximab-resistant sublines of HNSCC cell lines for investigating the mechanism of acquired resistance to cetuximab. Zebrafish model was applied for evaluating the synergistic effect of combinatory drugs for overcoming cetuximab resistance.Results: The cetuximab-resistant HNSCC cells undergo a Snail-induced epithelial-mesenchymal transition. Mechanistically, Snail induces the expression of lymphotoxin-β (LTβ), a TNF superfamily protein that activates NF-κB, and protein arginine methyltransferase 1 (PRMT1), an arginine methyltransferase that methylates EGFR. LTβ interacts with methylated EGFR to promote its ligand-binding ability and dimerization. Furthermore, LTβ activates the NF-κB pathway through a LTβ receptor-independent mechanism. Combination of an EGFR tyrosine kinase inhibitor and a NF-κB inhibitor effectively suppressed cetuximab-resistant HNSCC and interfering with the EGFR-LTβ interaction reverses resistance.Conclusions: Our findings elucidate the mechanism of driver gene mutations-independent mechanism of acquired resistance to cetuximab in HNSCC and also provide potential strategies for combating cetuximab resistance. Clin Cancer Res; 23(15); 4388-401. ©2017 AACR.
Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes