MyD88-Dependent Signaling Decreases the Antitumor Efficacy of Epidermal Growth Factor Receptor Inhibition in Head and Neck Cancer Cells

Adam T Koch; Laurie Love-Homan; Madelyn Espinosa-Cotton; Aditya Stanam; Andrean L Simons

doi:10.1158/0008-5472.CAN-14-2061

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MyD88-Dependent Signaling Decreases the Antitumor Efficacy of Epidermal Growth Factor Receptor Inhibition in Head and Neck Cancer Cells

Journal article

Open access

Peer reviewed

MyD88-Dependent Signaling Decreases the Antitumor Efficacy of Epidermal Growth Factor Receptor Inhibition in Head and Neck Cancer Cells

Adam T Koch, Laurie Love-Homan, Madelyn Espinosa-Cotton, Aditya Stanam and Andrean L Simons

Cancer research (Chicago, Ill.), Vol.75(8), pp.1657-1667

04/15/2015

DOI: 10.1158/0008-5472.CAN-14-2061

PMCID: PMC4401635

PMID: 25712126

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Abstract

EGFR is upregulated in the majority of head and neck squamous cell carcinomas (HNSCC). However, many patients with HNSCC respond poorly to the EGFR inhibitors (EGFRI) cetuximab and erlotinib, despite tumor expression of EGFR. Gene expression analysis of erlotinib-treated HNSCC cells revealed an upregulation of genes involved in MyD88-dependent signaling compared with their respective vehicle-treated cell lines. We therefore investigated whether MyD88-dependent signaling may reduce the antitumor efficacy of EGFRIs in HNSCC. Erlotinib significantly upregulated IL6 secretion in HNSCC cell lines, which our laboratory previously reported to result in reduced drug efficacy. Suppression of MyD88 expression blocked erlotinib-induced IL6 secretion in vitro and increased the antitumor activity of erlotinib in vivo. There was little evidence of Toll-like receptor or IL18 receptor involvement in erlotinib-induced IL6 secretion. However, suppression of IL1R signaling significantly reduced erlotinib-induced IL6 production. A time-dependent increase of IL1α but not IL1β was observed in response to erlotinib treatment, and IL1α blockade significantly increased the antitumor activity of erlotinib and cetuximab in vivo. A pan-caspase inhibitor reduced erlotinib-induced IL1α secretion, suggesting that IL1α was released because of cell death. Human HNSCC tumors showed higher IL1α mRNA levels compared with matched normal tissue, and IL1α was found to be negatively correlated with survival in patients with HNSCC. Overall, the IL1α/IL1R/MYD88/IL6 pathway may be responsible for the reduced antitumor efficacy of erlotinib and other EGFRIs, and blockade of IL1 signaling may improve the efficacy of EGFRIs in the treatment of HNSCC.

Erlotinib Hydrochloride

Apoptosis - drug effects

Carcinoma, Squamous Cell - genetics

Humans

Apoptosis - genetics

Male

Antineoplastic Agents - therapeutic use

Squamous Cell Carcinoma of Head and Neck

Antibodies, Monoclonal, Humanized - pharmacology

Female

Antineoplastic Agents - pharmacology

Tumor Cells, Cultured

Cetuximab

Antibodies, Monoclonal, Humanized - therapeutic use

ErbB Receptors - antagonists & inhibitors

Head and Neck Neoplasms - drug therapy

Treatment Outcome

Signal Transduction - genetics

Mice, Knockout

Drug Resistance, Neoplasm - genetics

Animals

Carcinoma, Squamous Cell - drug therapy

Mice, Nude

Quinazolines - therapeutic use

Myeloid Differentiation Factor 88 - physiology

Head and Neck Neoplasms - genetics

Mice

Quinazolines - pharmacology

Details

Title: Subtitle: MyD88-Dependent Signaling Decreases the Antitumor Efficacy of Epidermal Growth Factor Receptor Inhibition in Head and Neck Cancer Cells
Creators: Adam T Koch - Department of Pathology, The University of Iowa, Iowa City, Iowa. Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa
Laurie Love-Homan - Department of Pathology, The University of Iowa, Iowa City, Iowa. Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa
Madelyn Espinosa-Cotton - Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa. Free Radical and Radiation Biology Program, Department of Radiation Oncology, The University of Iowa, Iowa City, Iowa
Aditya Stanam - Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa. Interdisciplinary Human Toxicology Program, The University of Iowa, Iowa City, Iowa
Andrean L Simons - Department of Pathology, The University of Iowa, Iowa City, Iowa. Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa. Free Radical and Radiation Biology Program, Department of Radiation Oncology, The University of Iowa, Iowa City, Iowa. Interdisciplinary Human Toxicology Program, The University of Iowa, Iowa City, Iowa. Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, Iowa. andrean-simons@uiowa.edu
Resource Type: Journal article
Publication Details: Cancer research (Chicago, Ill.), Vol.75(8), pp.1657-1667
DOI: 10.1158/0008-5472.CAN-14-2061
PMID: 25712126
PMCID: PMC4401635
NLM abbreviation: Cancer Res
ISSN: 0008-5472
eISSN: 1538-7445
Publisher: United States
Grant note: R01DE024550 / NIDCR NIH HHS P30 ES005605 / NIEHS NIH HHS K01CA134941 / NCI NIH HHS T32 CA078586 / NCI NIH HHS K01 CA134941 / NCI NIH HHS R01 DE024550 / NIDCR NIH HHS
Language: English
Date published: 04/15/2015
Academic Unit: Oral Pathology, Radiology and Medicine; Pathology; Pharmaceutical Sciences and Experimental Therapeutics; Radiation Oncology
Record Identifier: 9984047898802771

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