{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Brunner A"],"funding":["Vetenskapsrådet","Radiumhemmets Forskningsfonder","Karolinska Institutet","Barncancerfonden","AstraZeneca","Cancerfonden"],"pagination":["e57894"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC7338058"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["9"],"pubmed_abstract":["Inhibition of WEE1 kinase by AZD1775 has shown promising results in clinical cancer trials, but markers predicting AZD1775 response are lacking. Here we analysed AZD1775 response in a panel of human breast cancer (BC) cell lines by global proteome/transcriptome profiling and identified two groups of basal-like BC (BLBCs): 'PTEN low' BLBCs were highly sensitive to AZD1775 and failed to recover following removal of AZD1775, while 'PTEN high' BLBCs recovered. AZD1775 induced phosphorylation of DNA-PK, protecting cells from replication-associated DNA damage and promoting cellular recovery. Deletion of DNA-PK or PTEN, or inhibition of DNA-PK sensitized recovering BLBCs to AZD1775 by abrogating replication arrest, allowing replication despite DNA damage. This was linked to reduced CHK1 activatio"],"journal":["eLife"],"pubmed_title":["PTEN and DNA-PK determine sensitivity and recovery in response to WEE1 inhibition in human breast cancer."],"pmcid":["PMC7338058"],"funding_grant_id":["PR2017-0161","191182","CAN2017/326","2014-3405","CAN2017/781, 19 0561 Pj","171183","TJ2018","AstraZeneca-SLL-KI Open Innovation grant #18122013"],"pubmed_authors":["Gazi M","Brunner A","Larsson LG","Frings O","Spruck C","Franco M","Fredlund E","Sangfelt O","Rantala JK","Lehtio J","Johansson H","Suryo Rahmanto A","Viiliainen J"],"additional_accession":[]},"is_claimable":false,"name":"PTEN and DNA-PK determine sensitivity and recovery in response to WEE1 inhibition in human breast cancer.","description":"Inhibition of WEE1 kinase by AZD1775 has shown promising results in clinical cancer trials, but markers predicting AZD1775 response are lacking. Here we analysed AZD1775 response in a panel of human breast cancer (BC) cell lines by global proteome/transcriptome profiling and identified two groups of basal-like BC (BLBCs): 'PTEN low' BLBCs were highly sensitive to AZD1775 and failed to recover following removal of AZD1775, while 'PTEN high' BLBCs recovered. AZD1775 induced phosphorylation of DNA-PK, protecting cells from replication-associated DNA damage and promoting cellular recovery. Deletion of DNA-PK or PTEN, or inhibition of DNA-PK sensitized recovering BLBCs to AZD1775 by abrogating replication arrest, allowing replication despite DNA damage. This was linked to reduced CHK1 activatio","dates":{"release":"2020-01-01T00:00:00Z","publication":"2020 Jul","modification":"2026-04-29T08:42:23.81Z","creation":"2024-11-21T05:58:03.464Z"},"accession":"S-EPMC7338058","cross_references":{"pubmed":["32628111"],"doi":["10.7554/eLife.57894"]}}