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

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

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

Cited by 19 publications

(19 citation statements)

References 33 publications

(48 reference statements)

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“…Interestingly, a recent publication emphasized the importance of IL1R-dependent signaling in HNSCCs. Therein, signaling from the IRAK1 adapter protein MyD88 was increased in response to erlotinib treatment in EGFR-amplified HNSCCs [ 22 ]. Furthermore, inhibition of IL1R signaling enhanced sensitivity to erlotinib treatment, thus supporting clinical potential for the targeting of TLR/IL1R signaling pathways in these cancers.…”

Section: Resultsmentioning

confidence: 99%

IRAK1 is a novel DEK transcriptional target and is essential for head and neck cancer cell survival

et al. 2015

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The chromatin-binding DEK protein was recently reported to promote the growth of HPV+ and HPV− head and neck squamous cell carcinomas (HNSCCs). Relevant cellular and molecular mechanism(s) controlled by DEK in HNSCC remain poorly understood. While DEK is known to regulate specific transcriptional targets, global DEK-dependent gene networks in HNSCC are unknown. To identify DEK transcriptional signatures we performed RNA-Sequencing (RNA-Seq) in HNSCC cell lines that were either proficient or deficient for DEK. Bioinformatic analyses and subsequent validation revealed that IRAK1, a regulator of inflammatory signaling, and IRAK1-dependent regulatory networks were significantly repressed upon DEK knockdown in HNSCC. According to TCGA data, 14% of HNSCC specimens overexpressed IRAK1, thus supporting possible oncogenic functions. Furthermore, genetic or pharmacologic inhibition of IRAK1 in HNSCC cell lines was sufficient to attenuate downstream signaling such as ERK1/2 and to induce HNSCC cell death by apoptosis. Finally, targeting DEK and IRAK1 simultaneously enhanced cell death as compared to targeting either alone. Our findings reveal that IRAK1 promotes cell survival and is an attractive therapeutic target in HNSCC cells. Thus, we propose a model wherein IRAK1 stimulates tumor signaling and phenotypes both independently and in conjunction with DEK.

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Section: Resultsmentioning

confidence: 99%

IRAK1 is a novel DEK transcriptional target and is essential for head and neck cancer cell survival

et al. 2015

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“…We observed that erlotinib treatment activated the IL-1 pathway in HNSCC cells which limited the efficacy of erlotinib in HNSCC cells [16]. The IL-1 pathway plays a central role in inflammatory responses by regulating the expression of various inflammatory genes in immune cells.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-1 blockade overcomes erlotinib resistance in head and neck squamous cell carcinoma

et al. 2016

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Erlotinib has demonstrated poor clinical response rates for head and neck squamous cell carcinoma (HNSCC) to date and the majority of respondents acquire resistance to erlotinib relatively quickly. To elucidate novel pathways involved in erlotinib resistance, we compared the gene expression profiles of erlotinib-resistant (ER) vs. erlotinib-sensitive (ES) HNSCC cell lines. Enrichment analysis of microarray data revealed a deregulation of the IL-1 signaling pathway in ER versus ES-HNSCC cells. Gene expression of interleukin-1 alpha (IL1A) and interleukin-1 beta (IL1B) were significantly upregulated by > 2 fold in ER-SQ20B and ER-CAL 27 cells compared to their respective ES-cells. Secretion of the IL-1 receptor antagonist (IL-1RA) was significantly reduced in ER-cells compared to ES-cells. Blockade of IL-1 signaling using a recombinant IL-1R antagonist (anakinra) was able to inhibit the growth of ER-SQ20B and ER-CAL 27 but not ES-SQ20B and ES-CAL 27 xenografts as a single agent and in combination with erlotinib. ER-SQ20B xenografts treated with anakinra ± erlotinib were found to be less vascularized than ER-SQ20B xenografts treated with water or erlotinib. Mice bearing ER-SQ20B xenografts had significantly lesser circulating levels of G-CSF and IL-1β when treated with anakinra ± erlotinib compared to those treated with water or erlotinib alone. Furthermore, augmented mRNA levels of IL1A or interleukin-1 receptor accessory protein (IL1RAP) were associated with shortened survival in HNSCC patients. Altogether, blockade of the IL-1 pathway using anakinra overcame erlotinib resistance in HNSCC xenografts and may represent a novel strategy to overcome EGFR inhibitor resistance for treatment of HNSCC patients.

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“…The functional analysis suggested an activation of inflammatory pathways that might be mediated by MyD88. Further experiments suggested the IL-1α/IL-1R/MYD88/IL-6 pathway as responsible for the reduced anti-tumor efficacy of erlotinib and other EGFR inhibitors [ 23 ]. However, in HNSCC cells these processes were upregulated, whereas in our experiments after 24 h treatment most genes involved in these pathways were downregulated.…”

Section: Discussionmentioning

confidence: 99%

Determining the effects of trastuzumab, cetuximab and afatinib by phosphoprotein, gene expression and phenotypic analysis in gastric cancer cell lines

et al. 2020

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Background Gastric cancer is the fifth most frequently diagnosed cancer and the third leading cause of cancer death worldwide. The molecular mechanisms of action for anti-HER-family drugs in gastric cancer cells are incompletely understood. We compared the molecular effects of trastuzumab and the other HER-family targeting drugs cetuximab and afatinib on phosphoprotein and gene expression level to gain insights into the regulated pathways. Moreover, we intended to identify genes involved in phenotypic effects of anti-HER therapies. Methods A time-resolved analysis of downstream intracellular kinases following EGF, cetuximab, trastuzumab and afatinib treatment was performed by Luminex analysis in the gastric cancer cell lines Hs746T, MKN1, MKN7 and NCI-N87. The changes in gene expression after treatment of the gastric cancer cell lines with EGF, cetuximab, trastuzumab or afatinib for 4 or 24 h were analyzed by RNA sequencing. Significantly enriched pathways and gene ontology terms were identified by functional enrichment analysis. Furthermore, effects of trastuzumab and afatinib on cell motility and apoptosis were analyzed by time-lapse microscopy and western blot for cleaved caspase 3. Results The Luminex analysis of kinase activity revealed no effects of trastuzumab, while alterations of AKT1, MAPK3, MEK1 and p70S6K1 activations were observed under cetuximab and afatinib treatment. On gene expression level, cetuximab mainly affected the signaling pathways, whereas afatinib had an effect on both signaling and cell cycle pathways. In contrast, trastuzumab had little effects on gene expression. Afatinib reduced average speed in MKN1 and MKN7 cells and induced apoptosis in NCI-N87 cells. Following treatment with afatinib, a list of 14 genes that might be involved in the decrease of cell motility and a list of 44 genes that might have a potential role in induction of apoptosis was suggested. The importance of one of these genes (HBEGF) as regulator of motility was confirmed by knockdown experiments. Conclusions Taken together, we described the different molecular effects of trastuzumab, cetuximab and afatinib on kinase activity and gene expression. The phenotypic changes following afatinib treatment were reflected by altered biological functions indicated by overrepresentation of gene ontology terms. The importance of identified genes for cell motility was validated in case of HBEGF.

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

Cited by 19 publications

References 33 publications

IRAK1 is a novel DEK transcriptional target and is essential for head and neck cancer cell survival

IRAK1 is a novel DEK transcriptional target and is essential for head and neck cancer cell survival

Interleukin-1 blockade overcomes erlotinib resistance in head and neck squamous cell carcinoma

Determining the effects of trastuzumab, cetuximab and afatinib by phosphoprotein, gene expression and phenotypic analysis in gastric cancer cell lines

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