Distinct apoptotic blocks mediate resistance to panHER inhibitors in HER2+breast cancer cells

dc.WoS.categoriesBiochemistry & Molecular Biology; Cell Biologyen_US
dc.contributor.authorGül, Özgür
dc.date.accessioned2020-06-23T11:58:47Z
dc.date.available2020-06-23T11:58:47Z
dc.date.issued2018-08
dc.description.abstractDespite the development of novel targeted therapies, de novo or acquired chemoresistance remains a significant factor for treatment failure in breast cancer therapeutics. Neratinib and dacomitinib are irreversible panHER inhibitors, which block their autophosphorylation and downstream signaling. Moreover, neratinib and dacomitinib have been shown to activate cell death in HER2-overexpressing cell lines. Here we showed that increased MCL1 and decreased BIM and PUMA mediated resistance to neratinib in ZR-75-30 and SKBR3 cells while increased BCL-XL and BCL-2 and decreased BIM and PUMA promoted neratinib resistance in BT474 cells. Cells were also cross-resistant to dacomitinib. BH3 profiles of HER2 + breast cancer cells efficiently predicted antiapoptotic protein dependence and development of resistance to panHER inhibitors. Reactivation of ERK1/2 was primarily responsible for acquired resistance in SKBR3 and ZR-75-30 cells. Adding specific ERK1/2 inhibitor SCH772984 to neratinib or dacomitinib led to increased apoptotic response in neratinib-resistant SKBR3 and ZR75-30 cells, but we did not detect a similar response in neratinib-resistant BT474 cells. Accordingly, suppression of BCL-2/BCL-XL by ABT-737 was required in addition to ERK1/2 inhibition for neratinib- or dacomitinib-induced apoptosis in neratinib-resistant BT474 cells. Our results showed that different mitochondrial apoptotic blocks mediated acquired panHER inhibitor resistance in HER2 + breast cancer cell lines as well as highlighted the potential of BH3 profiling assay in prediction of panHER inhibitor resistance in breast cancer cells.en_US
dc.fullTextLevelFull Texten_US
dc.identifier.doi10.1016/j.bbamcr.2018.05.002en_US
dc.identifier.issn0006-3002
dc.identifier.issn0167-4889
dc.identifier.pmid29733883en_US
dc.identifier.scopus2-s2.0-85046623254en_US
dc.identifier.urihttps://hdl.handle.net/11411/2266
dc.identifier.urihttps://doi.org/10.1016/j.bbamcr.2018.05.002
dc.identifier.wosWOS:000436216900005en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.issue8en_US
dc.language.isoenen_US
dc.nationalInternationalen_US
dc.numberofauthors3en_US
dc.pages1073-1087en_US
dc.publisherELSEVIER SCIENCE BVen_US
dc.relation.ispartofBIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCHen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectBreast canceren_US
dc.subjectpanHERen_US
dc.subjectHER2en_US
dc.subjectNeratiniben_US
dc.subjectCell deathen_US
dc.subjectBCL-2en_US
dc.titleDistinct apoptotic blocks mediate resistance to panHER inhibitors in HER2+breast cancer cellsen_US
dc.typeArticleen_US
dc.volume1865en_US

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