Capitalizing on Cancer Replication Stress by Preventing PAR Chain Turnover: A New Type of Synthetic Lethality

McDermott, Niamh; Buechelmaier, Erika S.; Powell, Simon N.

doi:10.1016/j.ccell.2019.02.011

Cited by 5 publications

(3 citation statements)

References 11 publications

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“…The concept that synthetic lethality derives from a distinct lesion is further supported by the range of synthetic lethal combinations unrelated to DSB repair (Hanzlikova et al, 2018;McDermott et al, 2019;Pillay et al, 2019;Ward et al, 2017;. Moreover, the synthetic lethality between PARPi and XRCC1, FEN1 and BRCA deficiency, or a PCNA OFP mutant and BRCA1 deficiency also implicates gaps due to OFP defects as the sensitizing lesion (Guo et al, 2020;Mengwasser et al, 2019;Stro ¨m et al, 2011;Thakar et al, 2020;van Wietmarschen and Nussenzweig, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…In summary, our findings establish a model to help further develop targeted treatment with PARPi, such that combined therapies maximize exposed lagging strand gaps. It will be crucial to consider whether gaps are the genetic vulnerability resensitizing PARPi-resistant cells (Ame ´et al, 2009;Gogola et al, 2018;Smith et al, 2015) or whether they underlie combinations that synergize with PARPi (Horton et al, 2014;McDermott et al, 2019;Michelena et al, 2018;Muvarak et al, 2016;Smith et al, 2015). The rationale for limiting PARPi to HR-defective cancers is in question because of significant clinical benefit across ovarian cancer patients regardless of BRCA status (Ledermann and Pujade-Lauraine, 2019;Pilie ´et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

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Replication gaps are a key determinant of PARP inhibitor synthetic lethality with BRCA deficiency

et al. 2021

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Replication gaps are a key determinant of PARP inhibitor synthetic lethality with BRCA deficiency

et al. 2021

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“…Poly(ADP-ribose) glycohydrolase (PARG) is a major cellular enzyme responsible for rapid de-PARylation of PARP synthesized PAR and generates monomeric ADP-ribose units [ 18 , 26 ]. Similar to PARP proteins, PARG is also recruited to the sites of damaged DNA and removes excessive PARylation to prevent cell death [ 27 ]. PARG deficiency impairs cells’ ability to repair both DNA single and double-strand breaks [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

CHK1 inhibitor induced PARylation by targeting PARG causes excessive replication and metabolic stress and overcomes chemoresistance in ovarian cancer

Acharya,

Mani,

Sah

et al. 2024

Cell Death Discov.

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Chemoresistance contributes to the majority of deaths in women with ovarian cancer (OC). Altered DNA repair and metabolic signaling is implicated in mediating therapeutic resistance. DNA damage checkpoint kinase 1 (CHK1) integrates cell cycle and DNA repair in replicating cells, and its inhibition causes replication stress, repair deficiency and cell cycle dysregulation. We observed elevated Poly-ADP-ribosylation (PAR) of proteins (PARylation) and subsequent decrease in cellular NAD+ levels in OC cells treated with the CHK1 inhibitor prexasertib, indicating activation of NAD+ dependent DNA repair enzymes poly-ADP-ribose polymerases (PARP1/2). While multiple PARP inhibitors are in clinical use in treating OC, tumor resistance to these drugs is highly imminent. We reasoned that inhibition of dePARylation by targeting Poly (ADP-ribose) glycohydrolase (PARG) would disrupt metabolic and DNA repair crosstalk to overcome chemoresistance. Although PARG inhibition (PARGi) trapped PARylation of the proteins and activated CHK1, it did not cause any significant OC cell death. However, OC cells deficient in CHK1 were hypersensitive to PARGi, suggesting a role for metabolic and DNA repair crosstalk in protection of OC cells. Correspondingly, OC cells treated with a combination of CHK1 and PARG inhibitors exhibited excessive replication stress-mediated DNA lesions, cell cycle dysregulation, and mitotic catastrophe compared to individual drugs. Interestingly, increased PARylation observed in combination treatment resulted in depletion of NAD+ levels. These decreased NAD+ levels were also paralleled with reduced aldehyde dehydrogenase (ALDH) activity, which requires NAD+ to maintain cancer stem cells. Furthermore, prexasertib and PARGi combinations exhibited synergistic cell death in OC cells, including an isogenic chemoresistant cell line and 3D organoid models of primary patient-derived OC cell lines. Collectively, our data highlight a novel crosstalk between metabolism and DNA repair involving replication stress and NAD+-dependent PARylation, and suggest a novel combination therapy of CHK1 and PARG inhibitors to overcome chemoresistance in OC.

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Cell cycle checkpoints and beyond: Exploiting the ATR/CHK1/WEE1 pathway for the treatment of PARP inhibitor–resistant cancer

Gupta

Huang

Horibata

et al. 2022

Pharmacological Research

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Capitalizing on Cancer Replication Stress by Preventing PAR Chain Turnover: A New Type of Synthetic Lethality

Cited by 5 publications

References 11 publications

Replication gaps are a key determinant of PARP inhibitor synthetic lethality with BRCA deficiency

Replication gaps are a key determinant of PARP inhibitor synthetic lethality with BRCA deficiency

CHK1 inhibitor induced PARylation by targeting PARG causes excessive replication and metabolic stress and overcomes chemoresistance in ovarian cancer

Cell cycle checkpoints and beyond: Exploiting the ATR/CHK1/WEE1 pathway for the treatment of PARP inhibitor–resistant cancer

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