Lymphotoxin-β Interacts with Methylated EGFR to Mediate Acquired Resistance to Cetuximab in Head and Neck Cancer

Dennis Shin-Shian Hsu, Wei-Lun Hwang, Chiou-Hwa Yuh, Chen-Hsi Chu, Yang-Hui Ho, Pon-Bo Chen, Han-Syuan Lin, Hua-Kuo Lin, Shih-Pei Wu, Chih-Yi Lin, Wen-Hao Hsu, Hsin-Yi Lan, Hsiao-Jung Wang, Shyh-Kuan Tai, Mien-Chie Hung, Muh-Hwa Yang

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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; 1-14. ©2017 AACR.

Original languageEnglish
JournalClinical Cancer Research
DOIs
Publication statusE-pub ahead of print - Feb 14 2017

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Lymphotoxin-alpha
Head and Neck Neoplasms
Mutation
Protein-Arginine N-Methyltransferases
Genes
Cetuximab
Epithelial-Mesenchymal Transition
Dimerization
Zebrafish
Protein-Tyrosine Kinases
Carcinoma, squamous cell of head and neck
Neoplasms
Research Design
Ligands
Cell Line

Keywords

  • Journal Article

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Lymphotoxin-β Interacts with Methylated EGFR to Mediate Acquired Resistance to Cetuximab in Head and Neck Cancer. / Hsu, Dennis Shin-Shian; Hwang, Wei-Lun; Yuh, Chiou-Hwa; Chu, Chen-Hsi; Ho, Yang-Hui; Chen, Pon-Bo; Lin, Han-Syuan; Lin, Hua-Kuo; Wu, Shih-Pei; Lin, Chih-Yi; Hsu, Wen-Hao; Lan, Hsin-Yi; Wang, Hsiao-Jung; Tai, Shyh-Kuan; Hung, Mien-Chie; Yang, Muh-Hwa.

In: Clinical Cancer Research, 14.02.2017.

Research output: Contribution to journalArticle

Hsu, DS-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 2017, 'Lymphotoxin-β Interacts with Methylated EGFR to Mediate Acquired Resistance to Cetuximab in Head and Neck Cancer', Clinical Cancer Research. https://doi.org/10.1158/1078-0432.CCR-16-1955
Hsu, Dennis Shin-Shian ; Hwang, Wei-Lun ; Yuh, Chiou-Hwa ; Chu, Chen-Hsi ; Ho, Yang-Hui ; Chen, Pon-Bo ; Lin, Han-Syuan ; Lin, Hua-Kuo ; Wu, Shih-Pei ; Lin, Chih-Yi ; Hsu, Wen-Hao ; Lan, Hsin-Yi ; Wang, Hsiao-Jung ; Tai, Shyh-Kuan ; Hung, Mien-Chie ; Yang, Muh-Hwa. / Lymphotoxin-β Interacts with Methylated EGFR to Mediate Acquired Resistance to Cetuximab in Head and Neck Cancer. In: Clinical Cancer Research. 2017.
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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; 1-14. {\circledC}2017 AACR.",
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T1 - Lymphotoxin-β Interacts with Methylated EGFR to Mediate Acquired Resistance to Cetuximab in Head and Neck Cancer

AU - Hsu, Dennis Shin-Shian

AU - Hwang, Wei-Lun

AU - Yuh, Chiou-Hwa

AU - Chu, Chen-Hsi

AU - Ho, Yang-Hui

AU - Chen, Pon-Bo

AU - Lin, Han-Syuan

AU - Lin, Hua-Kuo

AU - Wu, Shih-Pei

AU - Lin, Chih-Yi

AU - Hsu, Wen-Hao

AU - Lan, Hsin-Yi

AU - Wang, Hsiao-Jung

AU - Tai, Shyh-Kuan

AU - Hung, Mien-Chie

AU - Yang, Muh-Hwa

N1 - ©2017 American Association for Cancer Research.

PY - 2017/2/14

Y1 - 2017/2/14

N2 - 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; 1-14. ©2017 AACR.

AB - 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; 1-14. ©2017 AACR.

KW - Journal Article

U2 - 10.1158/1078-0432.CCR-16-1955

DO - 10.1158/1078-0432.CCR-16-1955

M3 - Article

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

ER -