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Lymphotoxin-β Interacts with Methylated EGFR to Mediate Acquired Resistance to Cetuximab in Head and Neck Cancer.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2017 Aug 01; Vol. 23 (15), pp. 4388-4401. Date of Electronic Publication: 2017 Feb 14. - Publication Year :
- 2017
-
Abstract
- 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 .<br /> (©2017 American Association for Cancer Research.)
- Subjects :
- Animals
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
ErbB Receptors antagonists & inhibitors
Head and Neck Neoplasms genetics
Head and Neck Neoplasms pathology
Humans
Mice
Mutation
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
Squamous Cell Carcinoma of Head and Neck
Xenograft Model Antitumor Assays
Zebrafish
Zebrafish Proteins genetics
Carcinoma, Squamous Cell drug therapy
Epithelial-Mesenchymal Transition genetics
ErbB Receptors genetics
Head and Neck Neoplasms drug therapy
Lymphotoxin-beta genetics
NF-kappa B antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 23
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 28196873
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-16-1955