ZFIN ID: ZDB-PUB-170216-4
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):
Lin, Han-Syuan, Yuh, Chiou-Hwa (Cathy)
Carcinoma, Squamous Cell/drug therapy*
Carcinoma, Squamous Cell/genetics
Carcinoma, Squamous Cell/pathology
Cell Line, Tumor
Cetuximab/administration & dosage
Disease Models, Animal
Drug Resistance, Neoplasm/genetics
Epithelial-Mesenchymal Transition/drug effects
Head and Neck Neoplasms/drug therapy*
Head and Neck Neoplasms/genetics
Head and Neck Neoplasms/pathology
NF-kappa B/antagonists & inhibitors*
Protein Kinase Inhibitors/administration & dosage
Protein Kinase Inhibitors/adverse effects
Snail Family Transcription Factors/genetics
Xenograft Model Antitumor Assays
Full text @ Clin. Cancer Res.
In head and neck squamous cell carcinoma (HNSCC), the incidence of
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
resistance. Here, we investigated the driver gene mutation-independent mechanism for cetuximab resistance in HNSCC.
We used the
-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.
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.
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