TY - JOUR TI - PTEN and DNA-PK determine sensitivity and recovery in response to WEE1 inhibition in human breast cancer AU - Brunner, Andrä AU - Suryo Rahmanto, Aldwin AU - Johansson, Henrik AU - Franco, Marcela AU - Viiliäinen, Johanna AU - Gazi, Mohiuddin AU - Frings, Oliver AU - Fredlund, Erik AU - Spruck, Charles AU - Lehtiö, Janne AU - Rantala, Juha K AU - Larsson, Lars-Gunnar AU - Sangfelt, Olle A2 - Murphy, Maureen E VL - 9 PY - 2020 DA - 2020/07/06 SP - e57894 C1 - eLife 2020;9:e57894 DO - 10.7554/eLife.57894 UR - https://doi.org/10.7554/eLife.57894 AB - 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 activation, increased cyclin E levels and apoptosis. In conclusion, we identified PTEN and DNA-PK as essential regulators of replication checkpoint arrest in response to AZD1775 and defined PTEN as a promising biomarker for efficient WEE1 cancer therapy. KW - PTEN KW - DNA-PK KW - AZD1775 KW - basal-like breast cancer KW - WEE1 KW - cyclin E JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -