biostudies-literatureBrunner AVetenskapsrådetRadiumhemmets ForskningsfonderKarolinska InstitutetBarncancerfondenAstraZenecaCancerfondene57894https://www.ebi.ac.uk/biostudies/studies/S-EPMC7338058biostudies-literatureUnknown9Inhibition 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 activatioeLifePTEN and DNA-PK determine sensitivity and recovery in response to WEE1 inhibition in human breast cancer.PMC7338058PR2017-0161191182CAN2017/3262014-3405CAN2017/781, 19 0561 Pj171183TJ2018AstraZeneca-SLL-KI Open Innovation grant #18122013Gazi MBrunner ALarsson LGFrings OSpruck CFranco MFredlund ESangfelt ORantala JKLehtio JJohansson HSuryo Rahmanto AViiliainen JfalsePTEN and DNA-PK determine sensitivity and recovery in response to WEE1 inhibition in human breast cancer.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 activatio2020-01-01T00:00:00Z2020 Jul2026-04-29T08:42:23.81Z2024-11-21T05:58:03.464ZS-EPMC73380583262811110.7554/eLife.57894