title: Lymphotoxin-β Interacts with Methylated EGFR to Mediate Acquired Resistance to Cetuximab in Head and Neck Cancer.
abstract: Purpose:In head and neck squamous cell carcinoma (HNSCC), the incidence ofRASmutation, 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-mediatedde novoresistance. Here, we investigated the driver gene mutation-independent mechanism for cetuximab resistance in HNSCC.Experimental Design:We used thein vitro-selected andin 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.
authors.affiliation: Genome Research Center, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Dennis Shin-Shian
authors.initials: DS
authors.lastname: Hsu
authors.affiliation: The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Wei-Lun
authors.initials: WL
authors.lastname: Hwang
authors.affiliation: Institute of Molecular and Genome Medicine, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Chiou-Hwa
authors.initials: CH
authors.lastname: Yuh
authors.affiliation: Department of Life Science and Institute of Bioinformatics and Structural Biology, College of Life Science, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Chen-Hsi
authors.initials: CH
authors.lastname: Chu
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Yang-Hui
authors.initials: YH
authors.lastname: Ho
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Pon-Bo
authors.initials: PB
authors.lastname: Chen
authors.affiliation: Institute of Molecular and Genome Medicine, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Han-Syuan
authors.initials: HS
authors.lastname: Lin
authors.affiliation: Institute of Molecular and Genome Medicine, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Hua-Kuo
authors.initials: HK
authors.lastname: Lin
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Shih-Pei
authors.initials: SP
authors.lastname: Wu
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chih-Yi
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Wen-Hao
authors.initials: WH
authors.lastname: Hsu
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Lan
authors.affiliation: Division of Experimental Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Hsiao-Jung
authors.initials: HJ
authors.lastname: Wang
authors.affiliation: Department of Otolaryngology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Shyh-Kuan
authors.initials: SK
authors.lastname: Tai
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas.|Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung, Taiwan.|Department of Biotechnology, Asia University, Taichung, Taiwan.
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.affiliation: Genome Research Center, National Yang-Ming University, Taipei, Taiwan. mhyang2@vghtpe.gov.tw.|Genomics Research Center, Academia Sinica, Taipei, Taiwan.|Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.|Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Muh-Hwa
authors.initials: MH
authors.lastname: Yang
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000008:administration & dosage / Q000009:adverse effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D053308:Lymphotoxin-beta / Q000235:genetics*; D051379:Mice; D009154:Mutation; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D000071250:Snail Family Transcription Factors / Q000235:genetics; D000077195:Squamous Cell Carcinoma of Head and Neck; D023041:Xenograft Model Antitumor Assays; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics
chemical_list: C505886:LTB protein, human; D053308:Lymphotoxin-beta; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D012097:Repressor Proteins; D000071250:Snail Family Transcription Factors; D029961:Zebrafish Proteins; C514487:snai1a protein, zebrafish; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab