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 Andújar-Sánchez; 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 Andújar-Sánchez, Jiri Bartek, Massimo Lopes, Haico van Attikum, Piet Borst, Jos Jonkers^*, Sven Rottenberg

^*Corresponding author for this work

Cancer Research UK Manchester Institute

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

125 Downloads (Pure)

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.

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

Keywords

BRCA1
BRCA2
drug resistance
homologous recombination
PARG
PARP inhibitor
PARP1
PARylation
replication fork

Research Beacons, Institutes and Platforms

Manchester Cancer Research Centre

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ccell.2018.05.008

CANCER-CELL-D-18-00280R1_textAccepted author manuscript, 235 KBLicence: CC BY-NC-ND

Cite this

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., ... Rottenberg, S. (2018). Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality. Cancer Cell, 33(6), 1078-1093.e12. https://doi.org/10.1016/j.ccell.2018.05.008

@article{bec3de501e8e451fb60d686c55994739,

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. 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.",

keywords = "BRCA1, BRCA2, drug resistance, homologous recombination, PARG, PARP inhibitor, PARP1, PARylation, replication fork",

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 {Guerrero Llobet}, Sergi 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 And{\'u}jar-S{\'a}nchez 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--1093.e12",

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, Guerrero Llobet, S, 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, 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

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 - Guerrero Llobet, Sergi

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 - Andújar-Sánchez, 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. 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.

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. 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.

KW - BRCA1

KW - BRCA2

KW - drug resistance

KW - homologous recombination

KW - PARG

KW - PARP inhibitor

KW - PARP1

KW - PARylation

KW - replication fork

UR - http://www.scopus.com/inward/record.url?scp=85048007007&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2018.05.008

DO - 10.1016/j.ccell.2018.05.008

M3 - Article

AN - SCOPUS:85048007007

SN - 1535-6108

VL - 33

SP - 1078-1093.e12

JO - Cancer Cell

JF - Cancer Cell

IS - 6

ER -

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

Abstract

Keywords

Research Beacons, Institutes and Platforms

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this