Počet záznamů: 1  

Complementary genetic screens identify the E3 ubiquitin ligase CBLC, as a modifier of PARP inhibitor sensitivity

  1. 1.
    0455799 - UMG-J 2016 RIV US eng J - Článek v odborném periodiku
    Frankum, J. - Moudrý, P. - Brough, R. - Hodný, Zdeněk - Ashworth, A. - Bartek, Jiří - Lord, C.J.
    Complementary genetic screens identify the E3 ubiquitin ligase CBLC, as a modifier of PARP inhibitor sensitivity.
    OncoTarget. Roč. 6, č. 13 (2015), s. 10746-10758. ISSN 1949-2553
    Grant CEP: GA ČR GA13-17555S
    GRANT EU: European Commission HEALTH-F2-2010-259893
    Grant ostatní:Lundbeck Foundation(DK) R93-A8990; Danish Council for Independent Research(DK) DFF-1331-00262
    Institucionální podpora: RVO:68378050
    Klíčová slova: DNA damage response * ubiquitin-proteasome system * RNA interference screens * PARP inhibitors * CBLC
    Kód oboru RIV: EB - Genetika a molekulární biologie
    Impakt faktor: 5.008, rok: 2015

    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.
    Trvalý link: http://hdl.handle.net/11104/0256416