Publication

Premature mitotic entry induced by ATR inhibition potentiates olaparib inhibition-mediated genomic instability, inflammatory signaling, and cytotoxicity in BRCA2-deficient cancer cells

Schoonen, P. M., Kok, Y. P., Wierenga, E., Bakker, B., Foijer, F., Spierings, D. C. J. & A T M van Vugt, M., 21-Oct-2019, In : Molecular oncology. 19 p.

Research output: Contribution to journalArticleAcademicpeer-review

APA

Schoonen, P. M., Kok, Y. P., Wierenga, E., Bakker, B., Foijer, F., Spierings, D. C. J., & A T M van Vugt, M. (2019). Premature mitotic entry induced by ATR inhibition potentiates olaparib inhibition-mediated genomic instability, inflammatory signaling, and cytotoxicity in BRCA2-deficient cancer cells. Molecular oncology. https://doi.org/10.1002/1878-0261.12573

Author

Schoonen, Pepijn M ; Kok, Yannick P ; Wierenga, Elles ; Bakker, Bjorn ; Foijer, Floris ; Spierings, Diana C J ; A T M van Vugt, Marcel. / Premature mitotic entry induced by ATR inhibition potentiates olaparib inhibition-mediated genomic instability, inflammatory signaling, and cytotoxicity in BRCA2-deficient cancer cells. In: Molecular oncology. 2019.

Harvard

Schoonen, PM, Kok, YP, Wierenga, E, Bakker, B, Foijer, F, Spierings, DCJ & A T M van Vugt, M 2019, 'Premature mitotic entry induced by ATR inhibition potentiates olaparib inhibition-mediated genomic instability, inflammatory signaling, and cytotoxicity in BRCA2-deficient cancer cells', Molecular oncology. https://doi.org/10.1002/1878-0261.12573

Standard

Premature mitotic entry induced by ATR inhibition potentiates olaparib inhibition-mediated genomic instability, inflammatory signaling, and cytotoxicity in BRCA2-deficient cancer cells. / Schoonen, Pepijn M; Kok, Yannick P; Wierenga, Elles; Bakker, Bjorn; Foijer, Floris; Spierings, Diana C J; A T M van Vugt, Marcel.

In: Molecular oncology, 21.10.2019.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

Schoonen PM, Kok YP, Wierenga E, Bakker B, Foijer F, Spierings DCJ et al. Premature mitotic entry induced by ATR inhibition potentiates olaparib inhibition-mediated genomic instability, inflammatory signaling, and cytotoxicity in BRCA2-deficient cancer cells. Molecular oncology. 2019 Oct 21. https://doi.org/10.1002/1878-0261.12573


BibTeX

@article{64ea272321a24aa8bb66b9fc93300102,
title = "Premature mitotic entry induced by ATR inhibition potentiates olaparib inhibition-mediated genomic instability, inflammatory signaling, and cytotoxicity in BRCA2-deficient cancer cells",
abstract = "Poly(ADP-ribose) polymerase (PARP) inhibitors are selectively cytotoxic in cancer cells with defects in homologous recombination (HR) (e.g., due to BRCA1/2 mutations). However, not all HR-deficient tumors efficiently respond to PARP inhibition and often acquire resistance. It is therefore important to uncover how PARP inhibitors induce cytotoxicity and develop combination strategies to potentiate PARP inhibitor efficacy in HR-deficient tumors. In this study, we found that forced mitotic entry upon ATR inhibition potentiates cytotoxic effects of PARP inhibition using olaparib in BRCA2-depleted and Brca2 knockout cancer cell line models. Single DNA fiber analysis showed that ATR inhibition does not exacerbate replication fork degradation. Instead, we find ATR inhibitors accelerate mitotic entry, resulting in the formation of chromatin bridges and lagging chromosomes. Furthermore, using genome-wide single-cell sequencing, we show that ATR inhibition enhances genomic instability of olaparib-treated BRCA2-depleted cells. Inhibition of CDK1 to delay mitotic entry mitigated mitotic aberrancies and genomic instability upon ATR inhibition, underscoring the role of ATR in coordinating proper cell cycle timing in situations of DNA damage. Additionally, we show that olaparib treatment leads to increased numbers of micronuclei, which is accompanied by a cGAS/STING-associated inflammatory response in BRCA2-deficient cells. ATR inhibition further increased the numbers of cGAS-positive micronuclei and the extent of cytokine production in olaparib-treated BRCA2-deficient cancer cells. Altogether, we show that ATR inhibition induces premature mitotic entry and mediates synergistic cytotoxicity with PARP inhibition in HR-deficient cancer cells, which involves enhanced genomic instability and inflammatory signaling.",
keywords = "cell cycle, cGAS, STING, checkpoint, genomic instability, mitosis, single-cell sequencing, HOMOLOGY-DIRECTED REPAIR, REPLICATION STRESS, DNA-DAMAGE, RESISTANCE, RECOMBINATION, MUTATIONS, BRCA2, DEGRADATION, STABILITY, CHECKPOINT",
author = "Schoonen, {Pepijn M} and Kok, {Yannick P} and Elles Wierenga and Bjorn Bakker and Floris Foijer and Spierings, {Diana C J} and {A T M van Vugt}, Marcel",
note = "Molecular Oncology 2019 {\circledC} 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.",
year = "2019",
month = "10",
day = "21",
doi = "10.1002/1878-0261.12573",
language = "English",
journal = "Molecular oncology",
issn = "1574-7891",
publisher = "Wiley",

}

RIS

TY - JOUR

T1 - Premature mitotic entry induced by ATR inhibition potentiates olaparib inhibition-mediated genomic instability, inflammatory signaling, and cytotoxicity in BRCA2-deficient cancer cells

AU - Schoonen, Pepijn M

AU - Kok, Yannick P

AU - Wierenga, Elles

AU - Bakker, Bjorn

AU - Foijer, Floris

AU - Spierings, Diana C J

AU - A T M van Vugt, Marcel

N1 - Molecular Oncology 2019 © 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

PY - 2019/10/21

Y1 - 2019/10/21

N2 - Poly(ADP-ribose) polymerase (PARP) inhibitors are selectively cytotoxic in cancer cells with defects in homologous recombination (HR) (e.g., due to BRCA1/2 mutations). However, not all HR-deficient tumors efficiently respond to PARP inhibition and often acquire resistance. It is therefore important to uncover how PARP inhibitors induce cytotoxicity and develop combination strategies to potentiate PARP inhibitor efficacy in HR-deficient tumors. In this study, we found that forced mitotic entry upon ATR inhibition potentiates cytotoxic effects of PARP inhibition using olaparib in BRCA2-depleted and Brca2 knockout cancer cell line models. Single DNA fiber analysis showed that ATR inhibition does not exacerbate replication fork degradation. Instead, we find ATR inhibitors accelerate mitotic entry, resulting in the formation of chromatin bridges and lagging chromosomes. Furthermore, using genome-wide single-cell sequencing, we show that ATR inhibition enhances genomic instability of olaparib-treated BRCA2-depleted cells. Inhibition of CDK1 to delay mitotic entry mitigated mitotic aberrancies and genomic instability upon ATR inhibition, underscoring the role of ATR in coordinating proper cell cycle timing in situations of DNA damage. Additionally, we show that olaparib treatment leads to increased numbers of micronuclei, which is accompanied by a cGAS/STING-associated inflammatory response in BRCA2-deficient cells. ATR inhibition further increased the numbers of cGAS-positive micronuclei and the extent of cytokine production in olaparib-treated BRCA2-deficient cancer cells. Altogether, we show that ATR inhibition induces premature mitotic entry and mediates synergistic cytotoxicity with PARP inhibition in HR-deficient cancer cells, which involves enhanced genomic instability and inflammatory signaling.

AB - Poly(ADP-ribose) polymerase (PARP) inhibitors are selectively cytotoxic in cancer cells with defects in homologous recombination (HR) (e.g., due to BRCA1/2 mutations). However, not all HR-deficient tumors efficiently respond to PARP inhibition and often acquire resistance. It is therefore important to uncover how PARP inhibitors induce cytotoxicity and develop combination strategies to potentiate PARP inhibitor efficacy in HR-deficient tumors. In this study, we found that forced mitotic entry upon ATR inhibition potentiates cytotoxic effects of PARP inhibition using olaparib in BRCA2-depleted and Brca2 knockout cancer cell line models. Single DNA fiber analysis showed that ATR inhibition does not exacerbate replication fork degradation. Instead, we find ATR inhibitors accelerate mitotic entry, resulting in the formation of chromatin bridges and lagging chromosomes. Furthermore, using genome-wide single-cell sequencing, we show that ATR inhibition enhances genomic instability of olaparib-treated BRCA2-depleted cells. Inhibition of CDK1 to delay mitotic entry mitigated mitotic aberrancies and genomic instability upon ATR inhibition, underscoring the role of ATR in coordinating proper cell cycle timing in situations of DNA damage. Additionally, we show that olaparib treatment leads to increased numbers of micronuclei, which is accompanied by a cGAS/STING-associated inflammatory response in BRCA2-deficient cells. ATR inhibition further increased the numbers of cGAS-positive micronuclei and the extent of cytokine production in olaparib-treated BRCA2-deficient cancer cells. Altogether, we show that ATR inhibition induces premature mitotic entry and mediates synergistic cytotoxicity with PARP inhibition in HR-deficient cancer cells, which involves enhanced genomic instability and inflammatory signaling.

KW - cell cycle

KW - cGAS

KW - STING

KW - checkpoint

KW - genomic instability

KW - mitosis

KW - single-cell sequencing

KW - HOMOLOGY-DIRECTED REPAIR

KW - REPLICATION STRESS

KW - DNA-DAMAGE

KW - RESISTANCE

KW - RECOMBINATION

KW - MUTATIONS

KW - BRCA2

KW - DEGRADATION

KW - STABILITY

KW - CHECKPOINT

U2 - 10.1002/1878-0261.12573

DO - 10.1002/1878-0261.12573

M3 - Article

C2 - 31529615

JO - Molecular oncology

JF - Molecular oncology

SN - 1574-7891

ER -

ID: 97721918