Complementary genetic screens identify the E3 ubiquitin ligase CBLC, as a modifier of PARP inhibitor sensitivity.
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Embargo End Date
ICR Authors
Authors
Frankum, J
Moudry, P
Brough, R
Hodny, Z
Ashworth, A
Bartek, J
Lord, CJ
Moudry, P
Brough, R
Hodny, Z
Ashworth, A
Bartek, J
Lord, CJ
Document Type
Journal Article
Date
2015-05-10
Date Accepted
2015-02-20
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.
Citation
Oncotarget, 2015, 6 (13), pp. 10746 - 10758
Source Title
Publisher
IMPACT JOURNALS LLC
ISSN
1949-2553
eISSN
1949-2553
Collections
Research Team
Gene Function