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dc.contributor.authorEbert, Karolin
dc.contributor.authorZwingenberger, Gwen
dc.contributor.authorBarbaria, Elena
dc.contributor.authorKeller, Simone
dc.contributor.authorHeck, Corinna
dc.contributor.authorArnold, Rouven
dc.contributor.authorHollerieth, Vanessa
dc.contributor.authorMattes, Julian
dc.contributor.authorGeffers, Robert
dc.contributor.authorRaimúndez, Elba
dc.contributor.authorHasenauer, Jan
dc.contributor.authorLuber, Birgit
dc.date.accessioned2020-11-03T12:46:37Z
dc.date.available2020-11-03T12:46:37Z
dc.date.issued2020-10-28
dc.identifier.citationBMC Cancer. 2020 Oct 28;20(1):1039. doi: 10.1186/s12885-020-07540-7.en_US
dc.identifier.pmid33115415
dc.identifier.doi10.1186/s12885-020-07540-7
dc.identifier.urihttp://hdl.handle.net/10033/622551
dc.description.abstractBackground: 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.en_US
dc.language.isoenen_US
dc.publisherBMCen_US
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subjectAfatiniben_US
dc.subjectCetuximaben_US
dc.subjectGastric canceren_US
dc.subjectGene expressionen_US
dc.subjectMotilityen_US
dc.subjectPhosphoproteinen_US
dc.subjectTrastuzumaben_US
dc.titleDetermining the effects of trastuzumab, cetuximab and afatinib by phosphoprotein, gene expression and phenotypic analysis in gastric cancer cell lines.en_US
dc.typeArticleen_US
dc.identifier.eissn1471-2407
dc.contributor.departmentHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.en_US
dc.identifier.journalBMC canceren_US
dc.source.volume20
dc.source.issue1
dc.source.beginpage1039
dc.source.endpage
refterms.dateFOA2020-11-03T12:46:38Z
dc.source.journaltitleBMC cancer
dc.source.countryEngland


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