Kinome-wide RNAi screening for mediators of ABT-199 resistance in breast cancer cells identifies Wee1 as a novel therapeutic target

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dc.authoridkarakas, bahriye/0000-0001-9616-4656|KUTUK, OZGUR/0000-0001-9854-7220|AKA, YELİZ/0000-0002-1708-4779
dc.authorwosidkarakas, bahriye/GOK-0965-2022
dc.authorwosidKarakas, Bahriye/GOP-0970-2022
dc.authorwosidGul, Ozgur/A-7841-2011
dc.authorwosidKUTUK, OZGUR/AAH-1671-2019
dc.authorwosidAKA, YELİZ/JXM-3830-2024
dc.contributor.authorAka, Yeliz
dc.contributor.authorKarakas, Bahriye
dc.contributor.authorAcikbas, Ufuk
dc.contributor.authorBasaga, Huveyda
dc.contributor.authorGul, Ozgur
dc.contributor.authorKutuk, Ozgur
dc.date.accessioned2024-07-18T20:42:30Z
dc.date.available2024-07-18T20:42:30Z
dc.date.issued2021
dc.departmentİstanbul Bilgi Üniversitesien_US
dc.description.abstractAntiapoptotic and proapoptotic BCL-2 protein family members regulate mitochondrial apoptotic pathway. Small molecule inhibitors of antiapoptotic BCL-2 proteins including BCL-2-specific inhibitor ABT-199 (Venetoclax) are in clinical development. However, the efficiency of ABT-199 as a single agent in solid tumors is limited. We performed a high-throughput RNAi kinome screen targeting 691 kinases to identify potentially targetable kinases to enhance ABT-199 response in breast cancer cells. Our studies identified Wee1 as the primary target kinase to overcome resistance to ABT-199. Depletion of Wee1 by siRNA-mediated knockdown or inhibition of Wee1 by the small molecule Wee1 inhibitor AZD1775 sensitized SKBR3, MDA-MB-468, T47D and CAMA-1 breast cancer cells to ABT-199 along with decreased MCL1. BH3-only proteins PUMA and BIM functionally contribute to apoptosis signaling following co-targeting BCL-2 and Wee1. Suppression of Wee1 function increased mitochondrial cell death priming. Furthermore, we found that Wee1 inhibition altered MCL1 phosphorylation and protein stability, which led to HUWE1-mediated MCL1 degradation. Our findings suggest that Wee1 inhibition can overcome resistance to ABT-199 and provide a rationale for further translational investigation of BCL-2 inhibitor/Wee1 inhibitor combination in breast cancer.en_US
dc.identifier.doi10.1016/j.biocel.2021.106028
dc.identifier.issn1357-2725
dc.identifier.issn1878-5875
dc.identifier.pmid34171479en_US
dc.identifier.scopus2-s2.0-85109525795en_US
dc.identifier.scopusqualityQ2en_US
dc.identifier.urihttps://doi.org/10.1016/j.biocel.2021.106028
dc.identifier.urihttps://hdl.handle.net/11411/7296
dc.identifier.volume137en_US
dc.identifier.wosWOS:000730864000006en_US
dc.identifier.wosqualityQ2en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherPergamon-Elsevier Science Ltden_US
dc.relation.ispartofInternational Journal of Biochemistry & Cell Biologyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccessen_US
dc.subjectBreast Canceren_US
dc.subjectBcl-2en_US
dc.subjectMcl1en_US
dc.subjectPumaen_US
dc.subjectBımen_US
dc.subjectKinomeen_US
dc.subjectSirnaen_US
dc.subjectWee1en_US
dc.subjectCell Deathen_US
dc.subjectAbt-199en_US
dc.subjectAzd1775en_US
dc.subjectInhibitionen_US
dc.subjectBcl-2en_US
dc.subjectKinaseen_US
dc.subjectApoptosisen_US
dc.subjectMcl-1en_US
dc.subjectMk-1775en_US
dc.subjectProteinsen_US
dc.subjectPathwaysen_US
dc.subjectSurvivalen_US
dc.subjectLigaseen_US
dc.titleKinome-wide RNAi screening for mediators of ABT-199 resistance in breast cancer cells identifies Wee1 as a novel therapeutic targeten_US
dc.typeArticleen_US

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