PTEN and DNA-PK determine sensitivity and recovery in response to WEE1 inhibition in human breast cancer.
Andrä BrunnerAldwin Suryo RahmantoHenrik JohanssonMarcela FrancoJohanna ViiliäinenMohiuddin GaziOliver FringsErik FredlundCharles SpruckJanne LehtiöJuha K RantalaLars-Gunnar LarssonOlle SangfeltPublished in: eLife (2020)
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.
Keyphrases
- dna damage
- circulating tumor
- cell proliferation
- pi k akt
- cell free
- single molecule
- cell cycle
- oxidative stress
- endothelial cells
- cell cycle arrest
- cancer therapy
- nucleic acid
- single cell
- signaling pathway
- induced pluripotent stem cells
- squamous cell carcinoma
- high glucose
- rna seq
- circulating tumor cells
- genome wide
- papillary thyroid
- transcription factor
- pluripotent stem cells
- childhood cancer