Adaptive ERK signalling activation in response to therapy and in silico prognostic evaluation of EGFR-MAPK in HNSCC
Background Head and neck squamous cell carcinoma (HNSCC) patients frequently develop treatment resistance to cetuximab, a monoclonal antibody against EGFR, as well as radiotherapy. Here we addressed extracellular signal-regulated kinase 1/2 (ERK1/2) regulation by cetuximab or fractionated irradiatio...
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| Veröffentlicht in: | British journal of cancer 2020-07, Vol.123 (2), p.288-297 |
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| creator | Rong, Chao Muller, Marie F. Xiang, Fang Jensen, Alexandra Weichert, Wilko Major, Gerald Plinkert, Peter K. Hess, Jochen Affolter, Annette |
| description | Background
Head and neck squamous cell carcinoma (HNSCC) patients frequently develop treatment resistance to cetuximab, a monoclonal antibody against EGFR, as well as radiotherapy. Here we addressed extracellular signal-regulated kinase 1/2 (ERK1/2) regulation by cetuximab or fractionated irradiation (IR) and conducted in silico prognostic evaluation of the EGFR-MAPK axis in HNSCC.
Methods
Expression of ERK1/2 phosphorylation (pERK1/2) was determined in HNSCC cell lines, which were treated with cetuximab or fractionated-IR. Furthermore, the effect of fractionated IR on pERK1/2 was confirmed in an ex vivo HNSCC tissue culture model. Expression and prognostic significance of EGFR-ERK axis was evaluated in a cohort of radiotherapy plus cetuximab-treated HNSCC. Correlations among EGFR-MAPK signalling components and association between transcript and protein expression profiles and patient survival in HNSCC were analysed using publicly available databases.
Results
ERK1/2 phosphorylation was rebounded by prolonged cetuximab administration and was induced by fractionated IR, which could be suppressed by a MEK inhibitor as a radiosensitiser. In silico assessments suggested that EGFR-MAPK cascade genes and proteins could predict HNSCC patients’ survival as a prognostic signature.
Conclusions
Activation of ERK1/2 signalling contributes to the cellular defence of HNSCC against cetuximab and fractionated IR treatment. EGFR-MAPK axis has a prognostic significance in HNSCC. |
| doi_str_mv | 10.1038/s41416-020-0892-9 |
| format | Article |
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Head and neck squamous cell carcinoma (HNSCC) patients frequently develop treatment resistance to cetuximab, a monoclonal antibody against EGFR, as well as radiotherapy. Here we addressed extracellular signal-regulated kinase 1/2 (ERK1/2) regulation by cetuximab or fractionated irradiation (IR) and conducted in silico prognostic evaluation of the EGFR-MAPK axis in HNSCC.
Methods
Expression of ERK1/2 phosphorylation (pERK1/2) was determined in HNSCC cell lines, which were treated with cetuximab or fractionated-IR. Furthermore, the effect of fractionated IR on pERK1/2 was confirmed in an ex vivo HNSCC tissue culture model. Expression and prognostic significance of EGFR-ERK axis was evaluated in a cohort of radiotherapy plus cetuximab-treated HNSCC. Correlations among EGFR-MAPK signalling components and association between transcript and protein expression profiles and patient survival in HNSCC were analysed using publicly available databases.
Results
ERK1/2 phosphorylation was rebounded by prolonged cetuximab administration and was induced by fractionated IR, which could be suppressed by a MEK inhibitor as a radiosensitiser. In silico assessments suggested that EGFR-MAPK cascade genes and proteins could predict HNSCC patients’ survival as a prognostic signature.
Conclusions
Activation of ERK1/2 signalling contributes to the cellular defence of HNSCC against cetuximab and fractionated IR treatment. EGFR-MAPK axis has a prognostic significance in HNSCC.</description><identifier>ISSN: 0007-0920</identifier><identifier>EISSN: 1532-1827</identifier><identifier>DOI: 10.1038/s41416-020-0892-9</identifier><identifier>PMID: 32424150</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>692/4017 ; 692/4028/67/1536 ; 692/53/2422 ; Animals ; Antibodies, Monoclonal, Humanized - pharmacology ; Biomedical and Life Sciences ; Biomedicine ; Cancer Research ; Cell culture ; Cell Line, Tumor ; Cetuximab - pharmacology ; Drug Resistance ; Drug Resistance, Neoplasm - drug effects ; Epidemiology ; Epidermal growth factor receptors ; ErbB Receptors - genetics ; Extracellular signal-regulated kinase ; Head & neck cancer ; Humans ; I.R. radiation ; Insect Proteins ; MAP kinase ; MAP Kinase Signaling System - drug effects ; Medical prognosis ; MEK inhibitors ; Mice ; Mitogen-Activated Protein Kinase 1 - genetics ; Mitogen-Activated Protein Kinase Kinases - genetics ; Molecular Medicine ; Monoclonal antibodies ; Oncology ; Phosphorylation ; Prognosis ; Protein Kinase Inhibitors - pharmacology ; Radiation therapy ; Squamous cell carcinoma ; Squamous Cell Carcinoma of Head and Neck - genetics ; Squamous Cell Carcinoma of Head and Neck - pathology ; Targeted cancer therapy ; Tissue culture ; Transcription ; Treatment resistance ; Xenograft Model Antitumor Assays</subject><ispartof>British journal of cancer, 2020-07, Vol.123 (2), p.288-297</ispartof><rights>The Author(s) 2020</rights><rights>The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>The Author(s) 2020. This work is published under https://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c498t-fdee5611fbfef40eab8dabeb8173b51b118b3acafd53a520e4f8c795e7788cfa3</citedby><cites>FETCH-LOGICAL-c498t-fdee5611fbfef40eab8dabeb8173b51b118b3acafd53a520e4f8c795e7788cfa3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374086/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374086/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27923,27924,41487,42556,51318,53790,53792</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32424150$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rong, Chao</creatorcontrib><creatorcontrib>Muller, Marie F.</creatorcontrib><creatorcontrib>Xiang, Fang</creatorcontrib><creatorcontrib>Jensen, Alexandra</creatorcontrib><creatorcontrib>Weichert, Wilko</creatorcontrib><creatorcontrib>Major, Gerald</creatorcontrib><creatorcontrib>Plinkert, Peter K.</creatorcontrib><creatorcontrib>Hess, Jochen</creatorcontrib><creatorcontrib>Affolter, Annette</creatorcontrib><title>Adaptive ERK signalling activation in response to therapy and in silico prognostic evaluation of EGFR-MAPK in HNSCC</title><title>British journal of cancer</title><addtitle>Br J Cancer</addtitle><addtitle>Br J Cancer</addtitle><description>Background
Head and neck squamous cell carcinoma (HNSCC) patients frequently develop treatment resistance to cetuximab, a monoclonal antibody against EGFR, as well as radiotherapy. Here we addressed extracellular signal-regulated kinase 1/2 (ERK1/2) regulation by cetuximab or fractionated irradiation (IR) and conducted in silico prognostic evaluation of the EGFR-MAPK axis in HNSCC.
Methods
Expression of ERK1/2 phosphorylation (pERK1/2) was determined in HNSCC cell lines, which were treated with cetuximab or fractionated-IR. Furthermore, the effect of fractionated IR on pERK1/2 was confirmed in an ex vivo HNSCC tissue culture model. Expression and prognostic significance of EGFR-ERK axis was evaluated in a cohort of radiotherapy plus cetuximab-treated HNSCC. Correlations among EGFR-MAPK signalling components and association between transcript and protein expression profiles and patient survival in HNSCC were analysed using publicly available databases.
Results
ERK1/2 phosphorylation was rebounded by prolonged cetuximab administration and was induced by fractionated IR, which could be suppressed by a MEK inhibitor as a radiosensitiser. In silico assessments suggested that EGFR-MAPK cascade genes and proteins could predict HNSCC patients’ survival as a prognostic signature.
Conclusions
Activation of ERK1/2 signalling contributes to the cellular defence of HNSCC against cetuximab and fractionated IR treatment. EGFR-MAPK axis has a prognostic significance in HNSCC.</description><subject>692/4017</subject><subject>692/4028/67/1536</subject><subject>692/53/2422</subject><subject>Animals</subject><subject>Antibodies, Monoclonal, Humanized - pharmacology</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer Research</subject><subject>Cell culture</subject><subject>Cell Line, Tumor</subject><subject>Cetuximab - pharmacology</subject><subject>Drug Resistance</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Epidemiology</subject><subject>Epidermal growth factor receptors</subject><subject>ErbB Receptors - genetics</subject><subject>Extracellular signal-regulated kinase</subject><subject>Head & neck cancer</subject><subject>Humans</subject><subject>I.R. radiation</subject><subject>Insect Proteins</subject><subject>MAP kinase</subject><subject>MAP Kinase Signaling System - drug effects</subject><subject>Medical prognosis</subject><subject>MEK inhibitors</subject><subject>Mice</subject><subject>Mitogen-Activated Protein Kinase 1 - genetics</subject><subject>Mitogen-Activated Protein Kinase Kinases - genetics</subject><subject>Molecular Medicine</subject><subject>Monoclonal antibodies</subject><subject>Oncology</subject><subject>Phosphorylation</subject><subject>Prognosis</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Radiation therapy</subject><subject>Squamous cell carcinoma</subject><subject>Squamous Cell Carcinoma of Head and Neck - genetics</subject><subject>Squamous Cell Carcinoma of Head and Neck - pathology</subject><subject>Targeted cancer therapy</subject><subject>Tissue culture</subject><subject>Transcription</subject><subject>Treatment resistance</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0007-0920</issn><issn>1532-1827</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kV1vFCEYhYnR2LX6A7wxJF6jL8wwMDcmm832I60fqXpNGAamNFMYYXaT_vuymbbqhV4ROM85L3AQekvhA4VKfsw1rWlDgAEB2TLSPkMryitGqGTiOVoBgCDQMjhCr3K-KdsWpHiJjipWs5pyWKG87vU0-73F26sLnP0Q9Dj6MGBtyqmefQzYB5xsnmLIFs8Rz9c26ekO69AfpOxHbyKeUhxCzLM32O71uFus0eHt6ckV-bz-dnGAz75832xeoxdOj9m-eViP0c-T7Y_NGbn8enq-WV8SU7dyJq63ljeUus5ZV4PVnex1ZztJRdVx2lEqu0ob7Xpeac7A1k4a0XIrhJTG6eoYfVpyp113a3tjw5z0qKbkb3W6U1F79bcS_LUa4l6JStQgmxLw_iEgxV87m2d1E3ep_FBWrBYcoGkE_z_FuGCN5FAoulAmxZyTdU_3oKAObaqlTVXaVIc2VVs87_58wJPjsb4CsAXIRQqDTb9H_zv1HvVmq9o</recordid><startdate>20200721</startdate><enddate>20200721</enddate><creator>Rong, Chao</creator><creator>Muller, Marie F.</creator><creator>Xiang, Fang</creator><creator>Jensen, Alexandra</creator><creator>Weichert, Wilko</creator><creator>Major, Gerald</creator><creator>Plinkert, Peter K.</creator><creator>Hess, Jochen</creator><creator>Affolter, Annette</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7RV</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AN0</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>5PM</scope></search><sort><creationdate>20200721</creationdate><title>Adaptive ERK signalling activation in response to therapy and in silico prognostic evaluation of EGFR-MAPK in HNSCC</title><author>Rong, Chao ; Muller, Marie F. ; Xiang, Fang ; Jensen, Alexandra ; Weichert, Wilko ; Major, Gerald ; Plinkert, Peter K. ; Hess, Jochen ; Affolter, Annette</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c498t-fdee5611fbfef40eab8dabeb8173b51b118b3acafd53a520e4f8c795e7788cfa3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>692/4017</topic><topic>692/4028/67/1536</topic><topic>692/53/2422</topic><topic>Animals</topic><topic>Antibodies, Monoclonal, Humanized - pharmacology</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cancer Research</topic><topic>Cell culture</topic><topic>Cell Line, Tumor</topic><topic>Cetuximab - pharmacology</topic><topic>Drug Resistance</topic><topic>Drug Resistance, Neoplasm - drug effects</topic><topic>Epidemiology</topic><topic>Epidermal growth factor receptors</topic><topic>ErbB Receptors - genetics</topic><topic>Extracellular signal-regulated kinase</topic><topic>Head & neck cancer</topic><topic>Humans</topic><topic>I.R. radiation</topic><topic>Insect Proteins</topic><topic>MAP kinase</topic><topic>MAP Kinase Signaling System - drug effects</topic><topic>Medical prognosis</topic><topic>MEK inhibitors</topic><topic>Mice</topic><topic>Mitogen-Activated Protein Kinase 1 - genetics</topic><topic>Mitogen-Activated Protein Kinase Kinases - genetics</topic><topic>Molecular Medicine</topic><topic>Monoclonal antibodies</topic><topic>Oncology</topic><topic>Phosphorylation</topic><topic>Prognosis</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Radiation therapy</topic><topic>Squamous cell carcinoma</topic><topic>Squamous Cell Carcinoma of Head and Neck - genetics</topic><topic>Squamous Cell Carcinoma of Head and Neck - pathology</topic><topic>Targeted cancer therapy</topic><topic>Tissue culture</topic><topic>Transcription</topic><topic>Treatment resistance</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rong, Chao</creatorcontrib><creatorcontrib>Muller, Marie F.</creatorcontrib><creatorcontrib>Xiang, Fang</creatorcontrib><creatorcontrib>Jensen, Alexandra</creatorcontrib><creatorcontrib>Weichert, Wilko</creatorcontrib><creatorcontrib>Major, Gerald</creatorcontrib><creatorcontrib>Plinkert, Peter K.</creatorcontrib><creatorcontrib>Hess, Jochen</creatorcontrib><creatorcontrib>Affolter, Annette</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>British Nursing Database</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rong, Chao</au><au>Muller, Marie F.</au><au>Xiang, Fang</au><au>Jensen, Alexandra</au><au>Weichert, Wilko</au><au>Major, Gerald</au><au>Plinkert, Peter K.</au><au>Hess, Jochen</au><au>Affolter, Annette</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Adaptive ERK signalling activation in response to therapy and in silico prognostic evaluation of EGFR-MAPK in HNSCC</atitle><jtitle>British journal of cancer</jtitle><stitle>Br J Cancer</stitle><addtitle>Br J Cancer</addtitle><date>2020-07-21</date><risdate>2020</risdate><volume>123</volume><issue>2</issue><spage>288</spage><epage>297</epage><pages>288-297</pages><issn>0007-0920</issn><eissn>1532-1827</eissn><abstract>Background
Head and neck squamous cell carcinoma (HNSCC) patients frequently develop treatment resistance to cetuximab, a monoclonal antibody against EGFR, as well as radiotherapy. Here we addressed extracellular signal-regulated kinase 1/2 (ERK1/2) regulation by cetuximab or fractionated irradiation (IR) and conducted in silico prognostic evaluation of the EGFR-MAPK axis in HNSCC.
Methods
Expression of ERK1/2 phosphorylation (pERK1/2) was determined in HNSCC cell lines, which were treated with cetuximab or fractionated-IR. Furthermore, the effect of fractionated IR on pERK1/2 was confirmed in an ex vivo HNSCC tissue culture model. Expression and prognostic significance of EGFR-ERK axis was evaluated in a cohort of radiotherapy plus cetuximab-treated HNSCC. Correlations among EGFR-MAPK signalling components and association between transcript and protein expression profiles and patient survival in HNSCC were analysed using publicly available databases.
Results
ERK1/2 phosphorylation was rebounded by prolonged cetuximab administration and was induced by fractionated IR, which could be suppressed by a MEK inhibitor as a radiosensitiser. In silico assessments suggested that EGFR-MAPK cascade genes and proteins could predict HNSCC patients’ survival as a prognostic signature.
Conclusions
Activation of ERK1/2 signalling contributes to the cellular defence of HNSCC against cetuximab and fractionated IR treatment. EGFR-MAPK axis has a prognostic significance in HNSCC.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>32424150</pmid><doi>10.1038/s41416-020-0892-9</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 692/4017 692/4028/67/1536 692/53/2422 Animals Antibodies, Monoclonal, Humanized - pharmacology Biomedical and Life Sciences Biomedicine Cancer Research Cell culture Cell Line, Tumor Cetuximab - pharmacology Drug Resistance Drug Resistance, Neoplasm - drug effects Epidemiology Epidermal growth factor receptors ErbB Receptors - genetics Extracellular signal-regulated kinase Head & neck cancer Humans I.R. radiation Insect Proteins MAP kinase MAP Kinase Signaling System - drug effects Medical prognosis MEK inhibitors Mice Mitogen-Activated Protein Kinase 1 - genetics Mitogen-Activated Protein Kinase Kinases - genetics Molecular Medicine Monoclonal antibodies Oncology Phosphorylation Prognosis Protein Kinase Inhibitors - pharmacology Radiation therapy Squamous cell carcinoma Squamous Cell Carcinoma of Head and Neck - genetics Squamous Cell Carcinoma of Head and Neck - pathology Targeted cancer therapy Tissue culture Transcription Treatment resistance Xenograft Model Antitumor Assays |
| title | Adaptive ERK signalling activation in response to therapy and in silico prognostic evaluation of EGFR-MAPK in HNSCC |
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