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Ref Type Journal Article
PMID (25883215)
Authors Frankum J, Moudry P, Brough R, Hodny Z, Ashworth A, Bartek J, Lord CJ
Title Complementary genetic screens identify the E3 ubiquitin ligase CBLC, as a modifier of PARP inhibitor sensitivity.
Journal Oncotarget
Vol 6
Issue 13
Date 2015 May 10
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
CBLC NCBI CBL-3|CBL-SL|RNF57 CBLC, Cbl proto-oncogene C, is an ubiquitin ligase that targets activated receptor kinases for degradation (PMID: 10362357). Overexpression of Cblc has been observed in non-small cell lung cancer (PMID: 29945960), mutations have been identified in myeloproliferative neoplasms (PMID: 22315494), and Cblc may modulate response to PARP inhibitors (PMID: 25883215). Both: Oncogene and Tumor suppressor
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
CBLC dec exp breast cancer predicted - sensitive Olaparib Preclinical Actionable In a preclinical study, decreased Cblc expression through siRNA knockdown enhanced sensitivity to Lynparza (olaparib) in cultured breast cancer cell lines (PMID: 25883215). 25883215
CBLC dec exp osteosarcoma predicted - sensitive Olaparib Preclinical Actionable In a preclinical study, decreased Cblc expression through siRNA knockdown enhanced sensitivity to Lynparza (olaparib) in cultured osterosarcoma cell lines (PMID: 25883215). 25883215