Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality

Ewa Gogola; Alexandra A. Duarte; Julian R. de Ruiter; Wouter W. Wiegant; Jonas A. Schmid; Roebi de Bruijn; Dominic I. James; Sergi Guerrero Llobet; Daniel J. Vis; Stefano Annunziato; Bram van den Broek; Marco Barazas; Ariena Kersbergen; Marieke van de Ven; Madalena Tarsounas; Donald J. Ogilvie; Marcel van Vugt; Lodewyk F. A. Wessels; Jirina Bartkova; Irina Gromova; Miguel Andujar-Sanchez; Jiri Bartek; Massimo Lopes; Haico van Attikum; Piet Borst; Jos Jonkers; Sven Rottenberg

doi:10.1016/j.ccell.2018.05.008

Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality

Ewa Gogola, Alexandra A. Duarte, Julian R. de Ruiter, Wouter W. Wiegant, Jonas A. Schmid, Roebi de Bruijn, Dominic I. James, Sergi Guerrero Llobet, Daniel J. Vis, Stefano Annunziato, Bram van den Broek, Marco Barazas, Ariena Kersbergen, Marieke van de Ven, Madalena Tarsounas, Donald J. Ogilvie, Marcel van Vugt, Lodewyk F. A. Wessels, Jirina Bartkova, Irina GromovaMiguel Andujar-Sanchez, Jiri Bartek, Massimo Lopes, Haico van Attikum, Piet Borst, Jos Jonkers, Sven Rottenberg

Research output: Contribution to journal › Article › Academic › peer-review

241 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1078-1093e12
Number of pages	28
Journal	Cancer cell
Volume	33
Issue number	6
DOIs	https://doi.org/10.1016/j.ccell.2018.05.008
Publication status	Published - 11-Jun-2018

Keywords

DNA-DAMAGE-RESPONSE
REPLICATION FORK REVERSAL
CONDITIONAL MOUSE MODEL
POLY(ADP-RIBOSE) POLYMERASE
DEFICIENT CELLS
MAMMARY-TUMORS
BREAST-CANCER
HOMOLOGOUS RECOMBINATION
COMBINATION THERAPY
REPAIR

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Gogola, E., Duarte, A. A., de Ruiter, J. R., Wiegant, W. W., Schmid, J. A., de Bruijn, R., James, D. I., Llobet, S. G., 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., ... Rottenberg, S. (2018). Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality. Cancer cell, 33(6), 1078-1093e12. https://doi.org/10.1016/j.ccell.2018.05.008

@article{293fe7cc83f548478acde663700d0743,

title = "Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality",

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.",

keywords = "DNA-DAMAGE-RESPONSE, REPLICATION FORK REVERSAL, CONDITIONAL MOUSE MODEL, POLY(ADP-RIBOSE) POLYMERASE, DEFICIENT CELLS, MAMMARY-TUMORS, BREAST-CANCER, HOMOLOGOUS RECOMBINATION, COMBINATION THERAPY, REPAIR",

author = "Ewa Gogola and Duarte, {Alexandra A.} and {de Ruiter}, {Julian R.} and Wiegant, {Wouter W.} and Schmid, {Jonas A.} and {de Bruijn}, Roebi and James, {Dominic I.} and Llobet, {Sergi Guerrero} and Vis, {Daniel J.} and Stefano Annunziato and {van den Broek}, Bram and Marco Barazas and Ariena Kersbergen and {van de Ven}, Marieke and Madalena Tarsounas and Ogilvie, {Donald J.} and {van Vugt}, Marcel and Wessels, {Lodewyk F. A.} and Jirina Bartkova and Irina Gromova and Miguel Andujar-Sanchez and Jiri Bartek and Massimo Lopes and {van Attikum}, Haico and Piet Borst and Jos Jonkers and Sven Rottenberg",

year = "2018",

month = jun,

day = "11",

doi = "10.1016/j.ccell.2018.05.008",

language = "English",

volume = "33",

pages = "1078--1093e12",

journal = "Cancer cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "6",

}

Gogola, E, Duarte, AA, de Ruiter, JR, Wiegant, WW, Schmid, JA, de Bruijn, R, James, DI, Llobet, SG, Vis, DJ, Annunziato, S, van den Broek, B, Barazas, M, Kersbergen, A, van de Ven, M, Tarsounas, M, Ogilvie, DJ, van Vugt, M, Wessels, LFA, Bartkova, J, Gromova, I, Andujar-Sanchez, 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. 1078-1093e12. https://doi.org/10.1016/j.ccell.2018.05.008

TY - JOUR

T1 - Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality

AU - Gogola, Ewa

AU - Duarte, Alexandra A.

AU - de Ruiter, Julian R.

AU - Wiegant, Wouter W.

AU - Schmid, Jonas A.

AU - de Bruijn, Roebi

AU - James, Dominic I.

AU - Llobet, Sergi Guerrero

AU - Vis, Daniel J.

AU - Annunziato, Stefano

AU - van den Broek, Bram

AU - Barazas, Marco

AU - Kersbergen, Ariena

AU - van de Ven, Marieke

AU - Tarsounas, Madalena

AU - Ogilvie, Donald J.

AU - van Vugt, Marcel

AU - Wessels, Lodewyk F. A.

AU - Bartkova, Jirina

AU - Gromova, Irina

AU - Andujar-Sanchez, Miguel

AU - Bartek, Jiri

AU - Lopes, Massimo

AU - van Attikum, Haico

AU - Borst, Piet

AU - Jonkers, Jos

AU - Rottenberg, Sven

PY - 2018/6/11

Y1 - 2018/6/11

N2 - 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.

AB - 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.

KW - DNA-DAMAGE-RESPONSE

KW - REPLICATION FORK REVERSAL

KW - CONDITIONAL MOUSE MODEL

KW - POLY(ADP-RIBOSE) POLYMERASE

KW - DEFICIENT CELLS

KW - MAMMARY-TUMORS

KW - BREAST-CANCER

KW - HOMOLOGOUS RECOMBINATION

KW - COMBINATION THERAPY

KW - REPAIR

U2 - 10.1016/j.ccell.2018.05.008

DO - 10.1016/j.ccell.2018.05.008

M3 - Article

SN - 1535-6108

VL - 33

SP - 1078-1093e12

JO - Cancer cell

JF - Cancer cell

IS - 6

ER -

Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality

Abstract

Keywords

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