Based on a series of basic, preclinical and clinical studies, the Poly (ADP-ribose) Polymerase 1 (PARP1) inhibitor, olaparib, has recently been approved for use in ovarian cancer patients with BRCA1 or BRCA2 mutations. By identifying novel predictive biomarkers of tumour cell sensitivity to olaparib, it is possible that the utility of PARP inhibitors could be extended beyond this patient subgroup. Many of the known genetic determinants of PARP inhibitor response have key roles in DNA damage response (DDR) pathways. Although protein ubiquitylation is known to play an important role in regulating the DDR, the exact mechanisms by which this occurs are not fully understood. Using two parallel RNA interference-based screening approaches, we identified the E3 ubiquitin ligase, CBLC, as a candidate biomarker of response to olaparib. We validated this observation by demonstrating that silencing of CBLC causes increased sensitivity to olaparib in breast cancer cell line models and that defective homologous recombination (HR) DNA repair is the likely cause. This data provides an example of how defects in the ubiquitin machinery have the potential to influence the response of tumour cells to PARP inhibitors.
- MeSH
- časové faktory MeSH
- ftalaziny farmakologie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádory prsu farmakoterapie enzymologie genetika patologie MeSH
- oprava DNA MeSH
- PARP inhibitory farmakologie MeSH
- piperaziny farmakologie MeSH
- poly(ADP-ribosa)-polymerasy genetika metabolismus MeSH
- posttranslační úpravy proteinů MeSH
- protein BRCA2 genetika metabolismus MeSH
- protoonkogenní proteiny c-cbl genetika metabolismus MeSH
- regulace genové exprese u nádorů MeSH
- rekombinace genetická MeSH
- RNA interference MeSH
- signální transdukce účinky léků MeSH
- transfekce MeSH
- ubikvitinace MeSH
- viabilita buněk účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
