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

Gogola, Ewa; Duarte, Alexandra A.; Ruiter, Julian R. de; Wiegant, Wouter W.; Schmid, Jonas; Bruijn, Roebi de; James, Dominic I.; Llobet, Sergi Guerrero; Vis, Daniël J.; Annunziato, Stefano; Broek, Bram van den; Barazas, Marco; Kersbergen, Ariena; Ven, Marieke van de; Tarsounas, Madalena; Ogilvie, Donald; Vugt, Marcel A.T.M. van; Wessels, Lodewyk; Bártková, Jiřina; Gromova, Irina; Andújar-Sánchez, Miguel; Bártek, Jiří; Lopes, Massimo; Attikum, Haico van; Borst, Piet; Jonkers, Jos; Rottenberg, Sven

doi:10.1016/j.ccell.2018.05.008

Cited by 272 publications

(195 citation statements)

References 80 publications

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“…The RAD51 assay has some limitations: firstly, when PARPi sensitivity occurs via mechanisms that do not directly impact on the ability of cells to perform HRR, e.g., alterations in ATM (Chen et al , ; Davies et al , ; preprint: Balmus et al , ) or in the RNASEH2 complex (Zimmermann et al , ); secondly, when PARPi sensitivity occurs via mechanisms that preserve RAD51 foci formation, e.g., alterations in the MRN complex, RAD51AP1, polymerase eta, or ERCC1 (Kawamoto et al , ; Wiese et al , ; Oplustilova et al , ; Postel‐Vinay et al , ); thirdly, when HRR‐deficient tumors have acquired PARPi resistance via RAD51‐independent mechanisms such as loss of PARG, mutations in PARP1, or those that involve replication fork stabilization (Guillemette et al , ; Chaudhuri et al , ; Kais et al , ; Yazinski et al , ; Gogola et al , ; Michelena et al , ; Pettitt et al , ); fourthly, when a tumor has low proliferation index or low endogenous DNA damage, in which cases the assay would not be feasible.…”

Section: Discussionmentioning

confidence: 99%

A RAD 51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation

Castroviejo-Bermejo¹,

et al. 2018

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Poly(ADP‐ribose) polymerase (PARP) inhibitors (PARPi) are effective in cancers with defective homologous recombination DNA repair (HRR), including BRCA1/2‐related cancers. A test to identify additional HRR‐deficient tumors will help to extend their use in new indications. We evaluated the activity of the PARPi olaparib in patient‐derived tumor xenografts (PDXs) from breast cancer (BC) patients and investigated mechanisms of sensitivity through exome sequencing, BRCA1 promoter methylation analysis, and immunostaining of HRR proteins, including RAD51 nuclear foci. In an independent BC PDX panel, the predictive capacity of the RAD51 score and the homologous recombination deficiency (HRD) score were compared. To examine the clinical feasibility of the RAD51 assay, we scored archival breast tumor samples, including PALB2‐related hereditary cancers. The RAD51 score was highly discriminative of PARPi sensitivity versus PARPi resistance in BC PDXs and outperformed the genomic test. In clinical samples, all PALB2‐related tumors were classified as HRR‐deficient by the RAD51 score. The functional biomarker RAD51 enables the identification of PARPi‐sensitive BC and broadens the population who may benefit from this therapy beyond BRCA1/2‐related cancers.

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Section: Discussionmentioning

confidence: 99%

A RAD 51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation

Castroviejo-Bermejo¹,

et al. 2018

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“…As previously described (Gogola et al , ), mRNA‐seq was performed as follows. Quality and quantity of the total RNA were assessed by the 2100 Bioanalyzer using a Nano chip (Agilent, Santa Clara, CA).…”

Section: Methodsmentioning

confidence: 99%

Local rewiring of genome–nuclear lamina interactions by transcription

et al. 2020

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Transcriptionally inactive genes are often positioned at the nuclear lamina (NL), as part of large lamina‐associated domains (LADs). Activation of such genes is often accompanied by repositioning toward the nuclear interior. How this process works and how it impacts flanking chromosomal regions are poorly understood. We addressed these questions by systematic activation or inactivation of individual genes, followed by detailed genome‐wide analysis of NL interactions, replication timing, and transcription patterns. Gene activation inside LADs typically causes NL detachment of the entire transcription unit, but rarely more than 50–100 kb of flanking DNA, even when multiple neighboring genes are activated. The degree of detachment depends on the expression level and the length of the activated gene. Loss of NL interactions coincides with a switch from late to early replication timing, but the latter can involve longer stretches of DNA. Inactivation of active genes can lead to increased NL contacts. These extensive datasets are a resource for the analysis of LAD rewiring by transcription and reveal a remarkable flexibility of interphase chromosomes.

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“…Resistance to PARP inhibition can also arise from altered activity of PARP and PARP‐associated proteins. One example is loss of poly(ADP‐ribose) glycohydrolase (PARG) that has been shown to be a major resistance mechanism to PARP inhibition in Brca2 ‐mutated cells (Gogola et al ., ). Under unperturbed cellular conditions, PARG functions to remove poly(ADP‐ribose) chains generated by PARP1 at the site of DNA damage.…”

Section: Targeting Dna Repair In Colorectal Cancermentioning

confidence: 97%

“…When PARG activity is lost, the polymers are still present and HR‐mediated repair is still functional. This residual HR activity can counteract the effect of the PARPi and lead to resistance (Gogola et al ., ).…”

Section: Targeting Dna Repair In Colorectal Cancermentioning

confidence: 97%

Exploiting DNA repair defects in colorectal cancer

et al. 2019

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Colorectal cancer ( CRC ) is the third leading cause of cancer‐related deaths worldwide. Therapies that take advantage of defects in DNA repair pathways have been explored in the context of breast, ovarian, and other tumor types, but not yet systematically in CRC . At present, only immune checkpoint blockade therapies have been FDA approved for use in mismatch repair‐deficient colorectal tumors. Here, we discuss how systematic identification of alterations in DNA repair genes could provide new therapeutic opportunities for CRC s. Analysis of The Cancer Genome Atlas Colon Adenocarcinoma ( TCGA ‐ COAD ) and Rectal Adenocarcinoma ( TCGA ‐ READ ) PanCancer Atlas datasets identified 141 (out of 528) cases with putative driver mutations in 29 genes associated with DNA damage response and repair, including the mismatch repair and homologous recombination pathways. Genetic defects in these pathways might confer repair‐deficient characteristics, such as genomic instability in the absence of homologous recombination, which can be exploited. For example, inhibitors of poly( ADP )‐ribose polymerase are effectively used to treat cancers that carry mutations in BRCA 1 and/or BRCA 2 and have shown promising results in CRC preclinical studies. HR deficiency can also occur in cells with no detectable BRCA 1/ BRCA 2 mutations but exhibiting BRCA ‐ like phenotypes. DNA repair‐targeting therapies, such as ATR and CHK 1 inhibitors (which are most effective against cancers carrying ATM mutations), can be used in combination with current genotoxic chemotherapies in CRC s to further improve therapy response. Finally, therapies that target alternative DNA repair mechanisms, such as thiopurines, also have the potential to confer increased sensitivity to current chemotherapy regimens, thus expanding the spectrum of therapy options and potentially improving clinical outcomes for CRC patients.

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

Cited by 272 publications

References 80 publications

A RAD 51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation

A RAD 51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation

Local rewiring of genome–nuclear lamina interactions by transcription

Exploiting DNA repair defects in colorectal cancer

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