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dc.contributor.authorNormann, Lisa Svartdal
dc.contributor.authorHaugen, Mads
dc.contributor.authorHongisto, Vesa
dc.contributor.authorAure, Miriam Ragle
dc.contributor.authorLeivonen, Suvi-Katri
dc.contributor.authorKristensen, Vessela N.
dc.contributor.authorTahiri, Andliena
dc.contributor.authorEngebråten, Olav
dc.contributor.authorSahlberg, Guro Kristine Kleivi
dc.contributor.authorMælandsmo, Gunhild Mari
dc.date.accessioned2023-08-22T11:16:51Z
dc.date.available2023-08-22T11:16:51Z
dc.date.issued2023-01-27
dc.description.abstractHuman epidermal growth factor receptor 2-positive (HER2+) breast cancer is an aggressive subtype of this disease. Targeted treatment has improved outcome, but there is still a need for new therapeutic strategies as some patients respond poorly to treatment. Our aim was to identify compounds that substantially affect viability in HER2+ breast cancer cells in response to combinatorial treatment. We performed a high-throughput drug screen of 278 compounds in combination with trastuzumab and lapatinib using two HER2+ breast cancer cell lines (KPL4 and SUM190PT). The most promising drugs were validated in vitro and in vivo, and downstream molecular changes of the treatments were analyzed. The screen revealed multiple drugs that could be used in combination with lapatinib and/or trastuzumab. The Src-inhibitor dasatinib showed the largest combinatorial effect together with lapatinib in the KPL4 cell line compared to treatment with dasatinib alone (p < 0.01). In vivo, only lapatinib significantly reduced tumor growth (p < 0.05), whereas dasatinib alone, or in combination with lapatinib, did not show significant effects. Protein analyses of the treated xenografts showed significant alterations in protein levels compared to untreated controls, suggesting that all drugs reached the tumor and exerted a measurable effect. In silico analyses suggested activation of apoptosis and reduced activity of survival pathways by all treatments, but the opposite pattern was observed for the combinatorial treatment compared to lapatinib alone.en_US
dc.identifier.citationNormann, Haugen, Hongisto, Aure, Leivonen, Kristensen, Tahiri, Engebråten, Sahlberg, Mælandsmo. High-throughput screen in vitro identifies dasatinib as a candidate for combinatorial treatment with HER2-targeting drugs in breast cancer. PLOS ONE. 2023;18(1)en_US
dc.identifier.cristinIDFRIDAID 2145486
dc.identifier.doi10.1371/journal.pone.0280507
dc.identifier.issn1932-6203
dc.identifier.urihttps://hdl.handle.net/10037/30171
dc.language.isoengen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.journalPLOS ONE
dc.rights.accessRightsopenAccessen_US
dc.rights.holderCopyright 2023 The Author(s)en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0en_US
dc.rightsAttribution 4.0 International (CC BY 4.0)en_US
dc.titleHigh-throughput screen in vitro identifies dasatinib as a candidate for combinatorial treatment with HER2-targeting drugs in breast canceren_US
dc.type.versionpublishedVersionen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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Attribution 4.0 International (CC BY 4.0)
Med mindre det står noe annet, er denne innførselens lisens beskrevet som Attribution 4.0 International (CC BY 4.0)