title: 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.
authors.affiliation: The CRUK Gene Function Laboratory and Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
authors.forename: Jessica
authors.initials: J
authors.lastname: Frankum
authors.affiliation: Danish Cancer Society Research Center, Strandboulevarden, Copenhagen, Denmark.
authors.forename: Pavel
authors.initials: P
authors.lastname: Moudry
authors.affiliation: The CRUK Gene Function Laboratory and Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Brough
authors.affiliation: Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Videnska, Czech Republic.
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Hodny
authors.affiliation: The CRUK Gene Function Laboratory and Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.affiliation: Danish Cancer Society Research Center, Strandboulevarden, Copenhagen, Denmark.|Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Videnska, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
authors.affiliation: The CRUK Gene Function Laboratory and Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lord
mesh_terms: D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D010793:Phthalazines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics* / Q000378:metabolism*; D034622:RNA Interference; D011995:Recombination, Genetic; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D054875:Ubiquitination
chemical_list: D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D050721:Proto-Oncogene Proteins c-cbl; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C119570:CBLC protein, human; C531550:olaparib
keywords: CBLC; DNA damage response; PARP inhibitors; RNA interference screens; ubiquitin-proteasome system