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Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality
- Source :
- Cancer cell, 33(6), 1078-1093e12. CELL PRESS, Cancer Cell, 33(6), 1078, Gogola, E, Duarte, A A, de Ruiter, J R, Wiegant, W W, Schmid, J A, de Bruijn, R, James, D I, Guerrero Llobet, S, Vis, D J, Annunziato, S, van den Broek, B, Barazas, M, Kersbergen, A, van de Ven, M, Tarsounas, M, Ogilvie, D J, van Vugt, M, Wessels, L F A, Bartkova, J, Gromova, I, Andújar-Sánchez, M, Bartek, J, Lopes, M, van Attikum, H, Borst, P, Jonkers, J & Rottenberg, S 2018, ' Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality ', Cancer Cell, vol. 33, no. 6, pp. 1078-1093.e12 . https://doi.org/10.1016/j.ccell.2018.05.008, Cancer Cell
- Publication Year :
- 2018
-
Abstract
- Inhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have recently entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, drug resistance is a clinical hurdle, and we poorly understand how cancer cells escape the deadly effects of PARPi without restoring the HR pathway. By combining genetic screens with multi-omics analysis of matched PARPi-sensitive and -resistant Brca2-mutated mouse mammary tumors, we identified loss of PAR glycohydrolase (PARG) as a major resistance mechanism. We also found the presence of PARG-negative clones in a subset of human serous ovarian and triple-negative breast cancers. PARG depletion restores PAR formation and partially rescues PARP1 signaling. Importantly, PARG inactivation exposes vulnerabilities that can be exploited therapeutically. Gogola et al. show loss of poly(ADP-ribose) glycohydrolase (PARG) confers resistance of BRCA2-deficient tumor cells to PARP inhibition by restoring PAR formation, controlled DNA replication fork progression, and the recruitment of downstream DNA repair factors while sensitizing them to ionizing radiation and temozolomide.
- Subjects :
- 0301 basic medicine
Cancer Research
Poly (ADP-Ribose) Polymerase-1
homologous recombination
Synthetic lethality
POLY(ADP-RIBOSE) POLYMERASE
PARP1
Poly (ADP-Ribose) Polymerase Inhibitor
HOMOLOGOUS RECOMBINATION
Poly ADP Ribosylation
0302 clinical medicine
Mice, Knockout
Ovarian Neoplasms
0303 health sciences
PARG
Manchester Cancer Research Centre
BRCA1 Protein
CONDITIONAL MOUSE MODEL
3. Good health
Oncology
DNA-DAMAGE-RESPONSE
030220 oncology & carcinogenesis
PARP inhibitor
Female
Replication fork reversal
Mice, 129 Strain
Glycoside Hydrolases
Poly ADP ribose polymerase
DEFICIENT CELLS
MAMMARY-TUMORS
Breast Neoplasms
Poly(ADP-ribose) Polymerase Inhibitors
Biology
Article
03 medical and health sciences
Cell Line, Tumor
Animals
Humans
BREAST-CANCER
REPLICATION FORK REVERSAL
030304 developmental biology
REPAIR
drug resistance
ResearchInstitutes_Networks_Beacons/mcrc
Cell Biology
BRCA1
BRCA2
PARylation
COMBINATION THERAPY
030104 developmental biology
Cancer research
replication fork
Synthetic Lethal Mutations
Genetic screen
Subjects
Details
- Language :
- English
- ISSN :
- 15356108
- Database :
- OpenAIRE
- Journal :
- Cancer cell, 33(6), 1078-1093e12. CELL PRESS, Cancer Cell, 33(6), 1078, Gogola, E, Duarte, A A, de Ruiter, J R, Wiegant, W W, Schmid, J A, de Bruijn, R, James, D I, Guerrero Llobet, S, Vis, D J, Annunziato, S, van den Broek, B, Barazas, M, Kersbergen, A, van de Ven, M, Tarsounas, M, Ogilvie, D J, van Vugt, M, Wessels, L F A, Bartkova, J, Gromova, I, Andújar-Sánchez, M, Bartek, J, Lopes, M, van Attikum, H, Borst, P, Jonkers, J & Rottenberg, S 2018, ' Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality ', Cancer Cell, vol. 33, no. 6, pp. 1078-1093.e12 . https://doi.org/10.1016/j.ccell.2018.05.008, Cancer Cell
- Accession number :
- edsair.doi.dedup.....91600eafa0442e1aa03c9d3219b8cb58