Format

Send to

Choose Destination
Oncotarget. 2015 May 10;6(13):10746-58.

Complementary genetic screens identify the E3 ubiquitin ligase CBLC, as a modifier of PARP inhibitor sensitivity.

Author information

1
The CRUK Gene Function Laboratory and Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
2
Danish Cancer Society Research Center, Strandboulevarden, Copenhagen, Denmark.
3
Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Videnska, Czech Republic.

Abstract

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.

KEYWORDS:

CBLC; DNA damage response; PARP inhibitors; RNA interference screens; ubiquitin-proteasome system

PMID:
25883215
PMCID:
PMC4484416
DOI:
10.18632/oncotarget.3628
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Impact Journals, LLC Icon for PubMed Central
Loading ...
Support Center