Aka, YelizKarakas, BahriyeAcikbas, UfukBasaga, HuveydaGul, OzgurKutuk, Ozgur2024-07-182024-07-1820211357-27251878-5875https://doi.org/10.1016/j.biocel.2021.106028https://hdl.handle.net/11411/7296Antiapoptotic 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.eninfo:eu-repo/semantics/closedAccessBreast CancerBcl-2Mcl1PumaBımKinomeSirnaWee1Cell DeathAbt-199Azd1775InhibitionBcl-2KinaseApoptosisMcl-1Mk-1775ProteinsPathwaysSurvivalLigaseArticle2-s2.0-8510952579510.1016/j.biocel.2021.10602834171479Q2137Q2WOS:000730864000006