PTEN and DNA-PK determine sensitivity and recovery in response to WEE1 inhibition in human breast cancer.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 32628111.
- Also identified by DOI 10.7554/eLife.57894 and PMC identifier 7338058.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 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.
Medical subject headings
- Antineoplastic Agents
- Breast Neoplasms
- Cell Cycle Proteins
- DNA-Activated Protein Kinase
- PTEN Phosphohydrolase
- Protein-Tyrosine Kinases
- Pyrazoles
- Pyrimidinones