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, Björn; Foijer, Floris; Spierings, Diana C. J.; Vugt, Marcel A.T.M. van

doi:10.1002/1878-0261.12573

Cited by 71 publications

(74 citation statements)

References 68 publications

(95 reference statements)

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“…To measure premature mitotic upon ATR or WEE1 inhibition, cells were synchronized using a double thymidine block. In line with previous reports, ATR inhibition accelerated entry into mitosis, leading to a burst in mitotic cells 44 , whereas WEE1 inhibition did not 45 ( Supplementary Fig. 5G).…”

Section: T C a T C T T C T G T C C C T T C C C A G A A A A C C T A C Csupporting

confidence: 93%

“…5A, B). Although the observed activation of the ATR and WEE1 kinases did not completely prevent mitotic errors from occurring, inhibiting this response could enforce premature mitotic entry 44 , thereby exacerbate chromosome segregation errors in Cyclin E1-overexpressing or Cdc25Aoverexpressing cells. To test this, we induced overexpression of Cyclin E1 or Cdc25A in RPE-1-TP53 wt or RPE-1-TP53 −/− cells for 48 h, and subsequently treated the cells with ATR or WEE1 inhibitors for 8 h. Upon overexpression of Cyclin E1 in RPE-1-TP53 wt cells, WEE1 inhibition, but not ATR inhibition, resulted in a significant increase of mitotic aberrancies (Fig.…”

Section: T C a T C T T C T G T C C C T T C C C A G A A A A C C T A C Cmentioning

confidence: 96%

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Overexpression of Cyclin E1 or Cdc25A leads to replication stress, mitotic aberrancies, and increased sensitivity to replication checkpoint inhibitors

et al. 2020

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Oncogene-induced replication stress, for instance as a result of Cyclin E1 overexpression, causes genomic instability and has been linked to tumorigenesis. To survive high levels of replication stress, tumors depend on pathways to deal with these DNA lesions, which represent a therapeutically actionable vulnerability. We aimed to uncover the consequences of Cyclin E1 or Cdc25A overexpression on replication kinetics, mitotic progression, and the sensitivity to inhibitors of the WEE1 and ATR replication checkpoint kinases. We modeled oncogene-induced replication stress using inducible expression of Cyclin E1 or Cdc25A in non-transformed RPE-1 cells, either in a TP53 wild-type or TP53-mutant background. DNA fiber analysis showed Cyclin E1 or Cdc25A overexpression to slow replication speed. The resulting replication-derived DNA lesions were transmitted into mitosis causing chromosome segregation defects. Single cell sequencing revealed that replication stress and mitotic defects upon Cyclin E1 or Cdc25A overexpression resulted in genomic instability. ATR or WEE1 inhibition exacerbated the mitotic aberrancies induced by Cyclin E1 or Cdc25A overexpression, and caused cytotoxicity. Both these phenotypes were exacerbated upon p53 inactivation. Conversely, downregulation of Cyclin E1 rescued both replication kinetics, as well as sensitivity to ATR and WEE1 inhibitors. Taken together, Cyclin E1 or Cdc25A-induced replication stress leads to mitotic segregation defects and genomic instability. These mitotic defects are exacerbated by inhibition of ATR or WEE1 and therefore point to mitotic catastrophe as an underlying mechanism. Importantly, our data suggest that Cyclin E1 overexpression can be used to select patients for treatment with replication checkpoint inhibitors.

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Section: T C a T C T T C T G T C C C T T C C C A G A A A A C C T A C Csupporting

confidence: 93%

Section: T C a T C T T C T G T C C C T T C C C A G A A A A C C T A C Cmentioning

confidence: 96%

Overexpression of Cyclin E1 or Cdc25A leads to replication stress, mitotic aberrancies, and increased sensitivity to replication checkpoint inhibitors

et al. 2020

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“…These patients show improved prognosis, and in addition to increased genomic instability, these tumours have more frequent STING activation [243]. In the same context, inactivation of replicative stress response factors (PARP1 and/or ATR inhibition) enhances the cGAS-STING-mediated interferon response after BRCA2 inactivation in human cell lines [74,244]. Similar results have been shown in small cell lung cancer (SCLC) after the inhibition of either PARP1 or CHK1 [245,246].…”

Section: Implications For Immunotherapymentioning

confidence: 55%

Replication Stress, DNA Damage, Inflammatory Cytokines and Innate Immune Response

Ragu

Matos-Rodrigues

Lopez

2020

Genes

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Complete and accurate DNA replication is essential to genome stability maintenance during cellular division. However, cells are routinely challenged by endogenous as well as exogenous agents that threaten DNA stability. DNA breaks and the activation of the DNA damage response (DDR) arising from endogenous replication stress have been observed at pre-or early stages of oncogenesis and senescence. Proper detection and signalling of DNA damage are essential for the autonomous cellular response in which the DDR regulates cell cycle progression and controls the repair machinery. In addition to this autonomous cellular response, replicative stress changes the cellular microenvironment, activating the innate immune response that enables the organism to protect itself against the proliferation of damaged cells. Thereby, the recent descriptions of the mechanisms of the pro-inflammatory response activation after replication stress, DNA damage and DDR defects constitute important conceptual novelties. Here, we review the links of replication, DNA damage and DDR defects to innate immunity activation by pro-inflammatory paracrine effects, highlighting the implications for human syndromes and immunotherapies.Genes 2020, 11, 409 2 of 26 formed when nascent transcripts re-anneal to their template DNA, displacing the non-template strand as single-stranded DNA (ssDNA) [12]. Elevated R-loop levels cause DNA damage and genome instability. The loss of RNA processing and regulatory factors increases R-loop levels, causing R-loop dependent DNA damage in eukaryotic cells [13][14][15][16].DNA breaks and activation of the DNA damage response (DDR), arising from endogenous replication stress, have been observed at early or precancerous stages, and adaptation to replication stress plays an important role in tumour development [17][18][19][20]. The DDR protects genome stability through the precise coordination of a network of pathways, ensuring faithful transmission of genetic material, including DNA replication, repair and recombination, cell cycle checkpoint and chromosome segregation. Ultimately, these autonomous cell responses induce senescence or cell death [21][22][23][24][25]. All these processes prevent the proliferation of cells bearing DNA damage and/or genetic rearrangements. In agreement, syndromes caused by mutations in DDR and/or DNA repair factors are often associated with high genetic instability, cancer predisposition and premature ageing [24,[26][27][28]. In addition to these cell-autonomous responses, protective process(es) also act at the organism level. Such mechanism(s) involve the modification of the cellular microenvironment and ultimately the activation of innate immunity.The inflammatory response is a universal cell-intrinsic response to infections or tissue damage. Inflammation, which is triggered when innate immune cells detect infection, for example, eliminates the initial cause of cell injury, clears out necrotic cells and tissues damaged from the original insult and from the inflammatory process, and initiates ...

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“…MacKenzie et al proposed that cGAS localizes to micronuclei following rupture of the micronuclear envelope [5], and the subsequent release of these fragments into the cytosol induces a cGAS-mediated inflammatory response. The formation of micronuclei appears to be cell cycle dependent as it is greatly augmented by passage through the mitotic phase of the cell cycle, which results in the formation of chromatin bridges and mis-segregated chromosomes [1,5,52,53]. cGAS knockdown in combination with mitotic arrest increased micronuclei formation and chromosomal segregation defects, whereas inhibition of the mitotic inducer cyclin dependent kinase 1 (CDK1) or overexpression of the cell cycle inhibitor p21, which inhibits the transition of cells from G2 into the mitotic phase, reduced micronuclei formation [53,54].…”

Section: Micronuclei Formation and Breakdownmentioning

confidence: 99%

cGAS-STING pathway in oncogenesis and cancer therapeutics

et al. 2020

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The host innate immunity offers the first line of defense against infection. However, recent evidence shows that the host innate immunity is also critical in sensing the presence of cytoplasmic DNA derived from genomic instability events, such as DNA damage and defective cell cycle progression. This is achieved through the cyclic GMP-AMP synthase (cGAS)/Stimulator of interferon (IFN) genes (STING) pathway. Here we discuss recent insights into the regulation of this pathway in cancer immunosurveillance, and the downstream signaling cascades that coordinate immune cell recruitment to the tumor microenvironment to destroy transformed cells through cellular senescence or cell death programs. Its central role in immunosurveillance positions the cGAS-STING pathway as an attractive anti-cancer immunotherapeutic drug target for chemical agonists or vaccine adjuvants and suggests a key node to be targeted in a synthetic lethal approach. We also discuss adaptive mechanisms used by cancer cells to circumvent cGAS-STING signaling and present evidence linking chronic cGAS-STING activation to inflammation-induced carcinogenesis, cautioning against the use of activating the cGAS-STING pathway as an anti-tumor immunotherapy. A deeper mechanistic understanding of the cGAS-STING pathway will aid in the identification of potentially efficacious anti-cancer therapeutic targets. www.oncotarget.com Jackson for editing and providing comments on the manuscript.

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

Abstract: Abbreviations 53BP1, TP53-binding protein-1; ATR, ataxia telangiectasia and Rad3-related; BRCA1, breast cancer 1, early onset; BRCA2, breast cancer 2, early onset; CCL5, C-C motif chemokine-5; CDK1, cyclin-dependent kinase-

Cited by 71 publications

References 68 publications

Overexpression of Cyclin E1 or Cdc25A leads to replication stress, mitotic aberrancies, and increased sensitivity to replication checkpoint inhibitors

Overexpression of Cyclin E1 or Cdc25A leads to replication stress, mitotic aberrancies, and increased sensitivity to replication checkpoint inhibitors

Replication Stress, DNA Damage, Inflammatory Cytokines and Innate Immune Response

cGAS-STING pathway in oncogenesis and cancer therapeutics

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