Complementary genetic screens identify the E3 ubiquitin ligase CBLC, as a modifier of PARP inhibitor sensitivity.
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.
Collections
Subject
Cell Line, Tumor
Humans
Breast Neoplasms
Piperazines
Phthalazines
Poly(ADP-ribose) Polymerases
BRCA2 Protein
Transfection
Signal Transduction
Cell Survival
DNA Repair
Gene Expression Regulation, Neoplastic
RNA Interference
Protein Processing, Post-Translational
Recombination, Genetic
Dose-Response Relationship, Drug
Time Factors
Female
Proto-Oncogene Proteins c-cbl
Ubiquitination
Poly(ADP-ribose) Polymerase Inhibitors
Poly (ADP-Ribose) Polymerase-1
Research team
Gene Function
Language
eng
Date accepted
2015-02-20
License start date
2015-05
Citation
Oncotarget, 2015, 6 (13), pp. 10746 - 10758
Publisher
IMPACT JOURNALS LLC