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Complementary genetic screens identify the E3 ubiquitin ligase CBLC, as a modifier of PARP inhibitor sensitivity
Jessica Frankum1, Pavel Moudry2, Rachel Brough1
1The CRUK Gene Function Laboratory and Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
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.
Insights
Researchers identified CBLC as a potential biomarker for olaparib sensitivity in cancer. Silencing CBLC increased cancer cell sensitivity to olaparib, suggesting a role for the ubiquitin system in PARP inhibitor response.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Poly (ADP-ribose) Polymerase 1 (PARP1) inhibitors like olaparib are approved for BRCA-mutated ovarian cancer.
- Extending PARP inhibitor utility requires identifying new biomarkers for patient selection.
- DNA damage response (DDR) pathways are crucial for PARP inhibitor efficacy, with protein ubiquitylation playing a regulatory role.
Purpose of the Study:
- To identify novel predictive biomarkers of tumor cell sensitivity to olaparib.
- To investigate the role of the ubiquitin system in regulating DDR and PARP inhibitor response.
Main Methods:
- Utilized two parallel RNA interference-based screening approaches.
- Validated candidate biomarkers in breast cancer cell line models.
- Assessed olaparib sensitivity following gene silencing.
Main Results:
- Identified the E3 ubiquitin ligase CBLC as a candidate biomarker for olaparib response.
- Demonstrated that CBLC silencing increases sensitivity to olaparib in breast cancer cells.
- Linked this increased sensitivity to defective homologous recombination (HR) DNA repair.
Conclusions:
- CBLC is a potential predictive biomarker for olaparib response.
- Defects in the ubiquitin machinery, specifically CBLC, can influence tumor cell sensitivity to PARP inhibitors.
- This finding may help extend the application of PARP inhibitors to a broader patient population.
