Cetuximab augments cytotoxicity with poly (adp-ribose) polymerase inhibition in head and neck cancer
Overexpression of the epidermal growth factor receptor (EGFR) is a hallmark of head and neck cancers and confers increased resistance and inferior survival rates. Despite targeted agents against EGFR, such as cetuximab (C225), almost half of treated patients fail this therapy, necessitating novel th...
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| creator | Nowsheen, Somaira Bonner, James A Lobuglio, Albert F Trummell, Hoa Whitley, Alexander C Dobelbower, Michael C Yang, Eddy S |
| description | Overexpression of the epidermal growth factor receptor (EGFR) is a hallmark of head and neck cancers and confers increased resistance and inferior survival rates. Despite targeted agents against EGFR, such as cetuximab (C225), almost half of treated patients fail this therapy, necessitating novel therapeutic strategies. Poly (ADP-Ribose) polymerase (PARP) inhibitors (PARPi) have gained recent attention due to their unique selectivity in killing tumors with defective DNA repair. In this study, we demonstrate that C225 enhances cytotoxicity with the PARPi ABT-888 in UM-SCC1, UM-SCC6, and FaDu head and neck cancer cells. The mechanism of increased susceptibility to C225 and PARPi involves C225-mediated reduction of non-homologous end-joining (NHEJ)- and homologous recombination (HR)-mediated DNA double strand break (DSB) repair, the subsequent persistence of DNA damage, and activation of the intrinsic apoptotic pathway. By generating a DSB repair deficiency, C225 can render head and neck tumor cells susceptible to PARP inhibition. The combination of C225 and the PARPi ABT-888 can thus be an innovative treatment strategy to potentially improve outcomes in head and neck cancer patients. Furthermore, this strategy may also be feasible for other EGFR overexpressing tumors, including lung and brain cancers. |
| doi_str_mv | 10.1371/journal.pone.0024148 |
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Despite targeted agents against EGFR, such as cetuximab (C225), almost half of treated patients fail this therapy, necessitating novel therapeutic strategies. Poly (ADP-Ribose) polymerase (PARP) inhibitors (PARPi) have gained recent attention due to their unique selectivity in killing tumors with defective DNA repair. In this study, we demonstrate that C225 enhances cytotoxicity with the PARPi ABT-888 in UM-SCC1, UM-SCC6, and FaDu head and neck cancer cells. The mechanism of increased susceptibility to C225 and PARPi involves C225-mediated reduction of non-homologous end-joining (NHEJ)- and homologous recombination (HR)-mediated DNA double strand break (DSB) repair, the subsequent persistence of DNA damage, and activation of the intrinsic apoptotic pathway. By generating a DSB repair deficiency, C225 can render head and neck tumor cells susceptible to PARP inhibition. The combination of C225 and the PARPi ABT-888 can thus be an innovative treatment strategy to potentially improve outcomes in head and neck cancer patients. Furthermore, this strategy may also be feasible for other EGFR overexpressing tumors, including lung and brain cancers.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0024148</identifier><identifier>PMID: 21912620</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adenosine diphosphate ; Antibodies, Monoclonal - pharmacology ; Antibodies, Monoclonal, Humanized ; Antineoplastic agents ; Apoptosis ; Apoptosis - drug effects ; Attention ; Benzimidazoles - pharmacology ; Binding sites ; Biomarkers ; Brain ; Brain tumors ; Cancer ; Cancer therapies ; Care and treatment ; Cell Line, Tumor ; Cetuximab ; Clinical trials ; Cytotoxicity ; Deoxyribonucleic acid ; DNA ; DNA Damage ; DNA End-Joining Repair - drug effects ; DNA repair ; Double-strand break repair ; Drug dosages ; Drug Synergism ; Epidermal growth factor ; Epidermal growth factor receptors ; Epidermal growth factors ; Head ; Head & neck cancer ; Head and neck cancer ; Head and Neck Neoplasms - pathology ; Health aspects ; Homologous recombination ; Homologous Recombination - drug effects ; Homology ; Human papillomavirus ; Humans ; Hypotheses ; Immunotherapy ; Inhibition ; Lungs ; Medical prognosis ; Medicine ; Monoclonal antibodies ; Monosaccharides ; Non-homologous end joining ; Oncology ; Patients ; Poly(ADP-ribose) polymerase ; Poly(ADP-ribose) Polymerase Inhibitors ; Protein Kinase Inhibitors - pharmacology ; Receptor, Epidermal Growth Factor - antagonists & inhibitors ; Repair ; Ribose ; Survival ; Targeted cancer therapy ; Toxicity ; Tumor cells ; Tumors</subject><ispartof>PloS one, 2011-08, Vol.6 (8), p.e24148</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Nowsheen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Nowsheen et al. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c592t-b6277b25608137e51d7d4078a5ab429f441e8cbe01b4a856a4d245bc3f7259fd3</citedby><cites>FETCH-LOGICAL-c592t-b6277b25608137e51d7d4078a5ab429f441e8cbe01b4a856a4d245bc3f7259fd3</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/PMC3166164/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166164/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2095,2914,23846,27903,27904,53770,53772,79347,79348</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21912620$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Borgmann, Kerstin</contributor><creatorcontrib>Nowsheen, Somaira</creatorcontrib><creatorcontrib>Bonner, James A</creatorcontrib><creatorcontrib>Lobuglio, Albert F</creatorcontrib><creatorcontrib>Trummell, Hoa</creatorcontrib><creatorcontrib>Whitley, Alexander C</creatorcontrib><creatorcontrib>Dobelbower, Michael C</creatorcontrib><creatorcontrib>Yang, Eddy S</creatorcontrib><title>Cetuximab augments cytotoxicity with poly (adp-ribose) polymerase inhibition in head and neck cancer</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Overexpression of the epidermal growth factor receptor (EGFR) is a hallmark of head and neck cancers and confers increased resistance and inferior survival rates. Despite targeted agents against EGFR, such as cetuximab (C225), almost half of treated patients fail this therapy, necessitating novel therapeutic strategies. Poly (ADP-Ribose) polymerase (PARP) inhibitors (PARPi) have gained recent attention due to their unique selectivity in killing tumors with defective DNA repair. In this study, we demonstrate that C225 enhances cytotoxicity with the PARPi ABT-888 in UM-SCC1, UM-SCC6, and FaDu head and neck cancer cells. The mechanism of increased susceptibility to C225 and PARPi involves C225-mediated reduction of non-homologous end-joining (NHEJ)- and homologous recombination (HR)-mediated DNA double strand break (DSB) repair, the subsequent persistence of DNA damage, and activation of the intrinsic apoptotic pathway. By generating a DSB repair deficiency, C225 can render head and neck tumor cells susceptible to PARP inhibition. The combination of C225 and the PARPi ABT-888 can thus be an innovative treatment strategy to potentially improve outcomes in head and neck cancer patients. Furthermore, this strategy may also be feasible for other EGFR overexpressing tumors, including lung and brain cancers.</description><subject>Adenosine diphosphate</subject><subject>Antibodies, Monoclonal - pharmacology</subject><subject>Antibodies, Monoclonal, Humanized</subject><subject>Antineoplastic agents</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Attention</subject><subject>Benzimidazoles - pharmacology</subject><subject>Binding sites</subject><subject>Biomarkers</subject><subject>Brain</subject><subject>Brain tumors</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Care and treatment</subject><subject>Cell Line, Tumor</subject><subject>Cetuximab</subject><subject>Clinical trials</subject><subject>Cytotoxicity</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA Damage</subject><subject>DNA End-Joining Repair - drug effects</subject><subject>DNA repair</subject><subject>Double-strand break repair</subject><subject>Drug dosages</subject><subject>Drug Synergism</subject><subject>Epidermal growth factor</subject><subject>Epidermal growth factor receptors</subject><subject>Epidermal growth factors</subject><subject>Head</subject><subject>Head & neck cancer</subject><subject>Head and neck cancer</subject><subject>Head and Neck Neoplasms - pathology</subject><subject>Health aspects</subject><subject>Homologous recombination</subject><subject>Homologous Recombination - drug effects</subject><subject>Homology</subject><subject>Human papillomavirus</subject><subject>Humans</subject><subject>Hypotheses</subject><subject>Immunotherapy</subject><subject>Inhibition</subject><subject>Lungs</subject><subject>Medical prognosis</subject><subject>Medicine</subject><subject>Monoclonal antibodies</subject><subject>Monosaccharides</subject><subject>Non-homologous end joining</subject><subject>Oncology</subject><subject>Patients</subject><subject>Poly(ADP-ribose) polymerase</subject><subject>Poly(ADP-ribose) Polymerase Inhibitors</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Receptor, Epidermal Growth Factor - antagonists & inhibitors</subject><subject>Repair</subject><subject>Ribose</subject><subject>Survival</subject><subject>Targeted cancer therapy</subject><subject>Toxicity</subject><subject>Tumor cells</subject><subject>Tumors</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNp1Ustu1DAUjRCIlsIfIIjEBhYZ_I6zqVSNeFSqxAbWll-Z8ZDYwXag8_d4OmnVkUBe2Lr3nONzr05VvYZgBXELP-7CHL0cVlPwdgUAIpDwJ9U57DBqGAL46aP3WfUipR0AFHPGnldnCHYQlcZ5ZdY2z7dulKqW82a0Pqda73PI4dZpl_f1H5e39RSGff1emqmJToVkP9xVRhtlsrXzW6dcdsGXZ7210tTSm9pb_bPW0msbX1bPejkk-2q5L6ofnz99X39tbr59uV5f3TSadig3iqG2VYgywMuElkLTGgJaLqlUBHU9IdByrSyAikhOmSQGEao07ltEu97gi-rtUXcaQhLLgpKAGHCAOAKkIK6PCBPkTkyxDB73Ikgn7gohboSM2enBCqOYYQBSYFBLJCOcENQiBqjiBCBLi9bl8tusRmt02V2Uw4noace7rdiE3wJDxiA7mHm3CMTwa7Yp_8fygtrI4sr5PhQxPbqkxRVpGS-7IrigVv9AlWPs6HSJSO9K_YRAjgQdQ0rR9g_GIRCHgN2bEYeAiSVghfbm8dAPpPtE4b8DUs0C</recordid><startdate>20110830</startdate><enddate>20110830</enddate><creator>Nowsheen, Somaira</creator><creator>Bonner, James A</creator><creator>Lobuglio, Albert F</creator><creator>Trummell, Hoa</creator><creator>Whitley, Alexander C</creator><creator>Dobelbower, Michael C</creator><creator>Yang, Eddy S</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><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>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20110830</creationdate><title>Cetuximab augments cytotoxicity with poly (adp-ribose) polymerase inhibition in head and neck cancer</title><author>Nowsheen, Somaira ; Bonner, James A ; Lobuglio, Albert F ; Trummell, Hoa ; Whitley, Alexander C ; Dobelbower, Michael C ; Yang, Eddy S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c592t-b6277b25608137e51d7d4078a5ab429f441e8cbe01b4a856a4d245bc3f7259fd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Adenosine diphosphate</topic><topic>Antibodies, Monoclonal - 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Despite targeted agents against EGFR, such as cetuximab (C225), almost half of treated patients fail this therapy, necessitating novel therapeutic strategies. Poly (ADP-Ribose) polymerase (PARP) inhibitors (PARPi) have gained recent attention due to their unique selectivity in killing tumors with defective DNA repair. In this study, we demonstrate that C225 enhances cytotoxicity with the PARPi ABT-888 in UM-SCC1, UM-SCC6, and FaDu head and neck cancer cells. The mechanism of increased susceptibility to C225 and PARPi involves C225-mediated reduction of non-homologous end-joining (NHEJ)- and homologous recombination (HR)-mediated DNA double strand break (DSB) repair, the subsequent persistence of DNA damage, and activation of the intrinsic apoptotic pathway. By generating a DSB repair deficiency, C225 can render head and neck tumor cells susceptible to PARP inhibition. The combination of C225 and the PARPi ABT-888 can thus be an innovative treatment strategy to potentially improve outcomes in head and neck cancer patients. Furthermore, this strategy may also be feasible for other EGFR overexpressing tumors, including lung and brain cancers.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21912620</pmid><doi>10.1371/journal.pone.0024148</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2011-08, Vol.6 (8), p.e24148 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1308028204 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adenosine diphosphate Antibodies, Monoclonal - pharmacology Antibodies, Monoclonal, Humanized Antineoplastic agents Apoptosis Apoptosis - drug effects Attention Benzimidazoles - pharmacology Binding sites Biomarkers Brain Brain tumors Cancer Cancer therapies Care and treatment Cell Line, Tumor Cetuximab Clinical trials Cytotoxicity Deoxyribonucleic acid DNA DNA Damage DNA End-Joining Repair - drug effects DNA repair Double-strand break repair Drug dosages Drug Synergism Epidermal growth factor Epidermal growth factor receptors Epidermal growth factors Head Head & neck cancer Head and neck cancer Head and Neck Neoplasms - pathology Health aspects Homologous recombination Homologous Recombination - drug effects Homology Human papillomavirus Humans Hypotheses Immunotherapy Inhibition Lungs Medical prognosis Medicine Monoclonal antibodies Monosaccharides Non-homologous end joining Oncology Patients Poly(ADP-ribose) polymerase Poly(ADP-ribose) Polymerase Inhibitors Protein Kinase Inhibitors - pharmacology Receptor, Epidermal Growth Factor - antagonists & inhibitors Repair Ribose Survival Targeted cancer therapy Toxicity Tumor cells Tumors |
| title | Cetuximab augments cytotoxicity with poly (adp-ribose) polymerase inhibition in head and neck cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-22T02%3A26%3A06IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Cetuximab%20augments%20cytotoxicity%20with%20poly%20(adp-ribose)%20polymerase%20inhibition%20in%20head%20and%20neck%20cancer&rft.jtitle=PloS%20one&rft.au=Nowsheen,%20Somaira&rft.date=2011-08-30&rft.volume=6&rft.issue=8&rft.spage=e24148&rft.pages=e24148-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0024148&rft_dat=%3Cgale_plos_%3EA476881343%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1308028204&rft_id=info:pmid/21912620&rft_galeid=A476881343&rft_doaj_id=oai_doaj_org_article_db6d60150d274a64844272605b8402e5&rfr_iscdi=true |