The Influence of PARP, ATR, CHK1 Inhibitors on Premature Mitotic Entry and Genomic Instability in High-Grade Serous BRCAMUT and BRCAWT Ovarian Cancer Cells

Gralewska, Patrycja; Gajek, Arkadiusz; Rybaczek, Dorota; Marczak, Agnieszka; Rogalska, Aneta

doi:10.3390/cells11121889

Cited by 8 publications

(3 citation statements)

References 65 publications

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“…Hence, inhibition of PARP in cells with a decreased homologous recombination (HR) level, commonly indicating BRCA1/2 defects, may lead to the inability of SSB and DSB repair and further to programmed cell death [82]. It was demonstrated that the ATR-CHK1 pathway is vital for PARP-mediated response to DNA damage, according to their roles as restrainers of cell cycle progression by inhibition of CDK1 and CDK2 [83].…”

Section: Dna Damage Response and Replication Stressmentioning

confidence: 99%

Key Proteins of Replication Stress Response and Cell Cycle Control as Cancer Therapy Targets

Khamidullina,

Abramenko,

Bruter

et al. 2024

IJMS

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Replication stress (RS) is a characteristic state of cancer cells as they tend to exchange precision of replication for fast proliferation and increased genomic instability. To overcome the consequences of improper replication control, malignant cells frequently inactivate parts of their DNA damage response (DDR) pathways (the ATM-CHK2-p53 pathway), while relying on other pathways which help to maintain replication fork stability (ATR-CHK1). This creates a dependency on the remaining DDR pathways, vulnerability to further destabilization of replication and synthetic lethality of DDR inhibitors with common oncogenic alterations such as mutations of TP53, RB1, ATM, amplifications of MYC, CCNE1 and others. The response to RS is normally limited by coordination of cell cycle, transcription and replication. Inhibition of WEE1 and PKMYT1 kinases, which prevent unscheduled mitosis entry, leads to fragility of under-replicated sites. Recent evidence also shows that inhibition of Cyclin-dependent kinases (CDKs), such as CDK4/6, CDK2, CDK8/19 and CDK12/13 can contribute to RS through disruption of DNA repair and replication control. Here, we review the main causes of RS in cancers as well as main therapeutic targets—ATR, CHK1, PARP and their inhibitors.

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Section: Dna Damage Response and Replication Stressmentioning

confidence: 99%

Key Proteins of Replication Stress Response and Cell Cycle Control as Cancer Therapy Targets

Khamidullina,

Abramenko,

Bruter

et al. 2024

IJMS

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“…Moreover, it is known that p53or ATM-defective cells can only rely on ATR to avoid a mitotic catastrophe for excessive DNA damage accumulation after these treatments. Based on this knowledge, many ATR inhibitors (ATRi) are under preclinical and clinical investigation as monotherapies or in combination with other anticancer agents such as cisplatin, topotecan, gemcitabine, trabectedin, or PARPi [125,127,128,[276][277][278][279]. Preclinical results have shown inhibition of cell proliferation [127,129,136,137,139] and, in many cases, synergistic effects in combination with different drugs [124,125,128,[130][131][132][133][134][135]138,[140][141][142]145,279], which are summarized in Table 4.…”

Section: Atr Inhibitorsmentioning

confidence: 99%

“…Based on this knowledge, many ATR inhibitors (ATRi) are under preclinical and clinical investigation as monotherapies or in combination with other anticancer agents such as cisplatin, topotecan, gemcitabine, trabectedin, or PARPi [125,127,128,[276][277][278][279]. Preclinical results have shown inhibition of cell proliferation [127,129,136,137,139] and, in many cases, synergistic effects in combination with different drugs [124,125,128,[130][131][132][133][134][135]138,[140][141][142]145,279], which are summarized in Table 4. Clinical results have shown that ATR inhibitors (celarasertib, berzosertib, elimusertib, and gartisertib) were safe and well tolerated and presented preliminary antitumor activity in OC patients [201,280].…”

Section: Atr Inhibitorsmentioning

confidence: 99%

DNA Damage Response Alterations in Ovarian Cancer: From Molecular Mechanisms to Therapeutic Opportunities

Ovejero-Sánchez

González-Sarmiento

Herrero

2023

Cancers

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The DNA damage response (DDR), a set of signaling pathways for DNA damage detection and repair, maintains genomic stability when cells are exposed to endogenous or exogenous DNA-damaging agents. Alterations in these pathways are strongly associated with cancer development, including ovarian cancer (OC), the most lethal gynecologic malignancy. In OC, failures in the DDR have been related not only to the onset but also to progression and chemoresistance. It is known that approximately half of the most frequent subtype, high-grade serous carcinoma (HGSC), exhibit defects in DNA double-strand break (DSB) repair by homologous recombination (HR), and current evidence indicates that probably all HGSCs harbor a defect in at least one DDR pathway. These defects are not restricted to HGSCs; mutations in ARID1A, which are present in 30% of endometrioid OCs and 50% of clear cell (CC) carcinomas, have also been found to confer deficiencies in DNA repair. Moreover, DDR alterations have been described in a variable percentage of the different OC subtypes. Here, we overview the main DNA repair pathways involved in the maintenance of genome stability and their deregulation in OC. We also recapitulate the preclinical and clinical data supporting the potential of targeting the DDR to fight the disease.

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Targeting the DNA damage response in cancer

Federica,

Michela,

Giovanna

2024

MedComm

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DNA damage response (DDR) pathway is the coordinated cellular network dealing with the identification, signaling, and repair of DNA damage. It tightly regulates cell cycle progression and promotes DNA repair to minimize DNA damage to daughter cells. Key proteins involved in DDR are frequently mutated/inactivated in human cancers and promote genomic instability, a recognized hallmark of cancer. Besides being an intrinsic property of tumors, DDR also represents a unique therapeutic opportunity. Indeed, inhibition of DDR is expected to delay repair, causing persistent unrepaired breaks, to interfere with cell cycle progression, and to sensitize cancer cells to several DNA‐damaging agents, such as radiotherapy and chemotherapy. In addition, DDR defects in cancer cells have been shown to render these cells more dependent on the remaining pathways, which could be targeted very specifically (synthetic lethal approach). Research over the past two decades has led to the synthesis and testing of hundreds of small inhibitors against key DDR proteins, some of which have shown antitumor activity in human cancers. In parallel, the search for synthetic lethality interaction is broadening the use of DDR inhibitors. In this review, we discuss the state‐of‐art of ataxia‐telangiectasia mutated, ataxia‐telangiectasia‐and‐Rad3‐related protein, checkpoint kinase 1, Wee1 and Polθ inhibitors, highlighting the results obtained in the ongoing clinical trials both in monotherapy and in combination with chemotherapy and radiotherapy.

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The Influence of PARP, ATR, CHK1 Inhibitors on Premature Mitotic Entry and Genomic Instability in High-Grade Serous BRCAMUT and BRCAWT Ovarian Cancer Cells

Cited by 8 publications

References 65 publications

Key Proteins of Replication Stress Response and Cell Cycle Control as Cancer Therapy Targets

Key Proteins of Replication Stress Response and Cell Cycle Control as Cancer Therapy Targets

DNA Damage Response Alterations in Ovarian Cancer: From Molecular Mechanisms to Therapeutic Opportunities

Targeting the DNA damage response in cancer

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