Advances and perspectives of PARP inhibitors

Abstract DNA damage repair deficiency leads to the increased risk of genome instability and oncogenic transformation. In the meanwhile, this deficiency could be exploited for cancer treatment by inducing excessive genome instability and catastrophic DNA damage. Continuous DNA replication in cancer cells leads to higher demand of DNA repair components. Due to the oncogenic loss of some DNA repair effectors (e.g. BRCA) and incomplete DNA repair repertoire, some cancer cells are addicted to certain DNA repair pathways such as Poly (ADP-ribose) polymerase (PARP)-related single-strand break repair pathway. The interaction between BRCA and PARP is a form of synthetic lethal effect which means the simultaneously functional loss of two genes lead to cell death, while defect in any single gene has a slight effect on cell viability. Based on synthetic lethal theory, Poly (ADP-ribose) polymerase inhibitor (PARPi) was developed aiming to selectively target cancer cells harboring BRCA1/2 mutations. Recently, a growing body of evidence indicated that a broader population of patients could benefit from PARPi therapy far beyond those with germline BRCA1/2 mutated tumors. Numerous biomarkers including homologous recombination deficiency and high level of replication pressure also herald high sensitivity to PARPi treatment. Besides, a series of studies indicated that PARPi-involved combination therapy such as PARPi with additional chemotherapy therapy, immune checkpoint inhibitor, as well as targeted agent had a great advantage in overcoming PARPi resistance and enhancing PARPi efficacy. In this review, we summarized the advances of PARPi in clinical application. Besides, we highlighted multiple promising PARPi-based combination strategies in preclinical and clinical studies.

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RAD52 as a Potential Target for Synthetic Lethality-Based Anticancer Therapies

Cancers ◽

10.3390/cancers11101561 ◽

2019 ◽

Vol 11 (10) ◽

pp. 1561 ◽

Cited By ~ 12

Author(s):

Toma ◽

Sullivan-Reed ◽

Śliwiński ◽

Skorski

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Cancer Cells ◽

Tumor Cells ◽

Synthetic Lethality ◽

Lethal Effect ◽

Drug Induced ◽

Synthetic Lethal ◽

Repair Mechanisms ◽

Cancer Tumor

Alterations in DNA repair systems play a key role in the induction and progression of cancer. Tumor-specific defects in DNA repair mechanisms and activation of alternative repair routes create the opportunity to employ a phenomenon called “synthetic lethality” to eliminate cancer cells. Targeting the backup pathways may amplify endogenous and drug-induced DNA damage and lead to specific eradication of cancer cells. So far, the synthetic lethal interaction between BRCA1/2 and PARP1 has been successfully applied as an anticancer treatment. Although PARP1 constitutes a promising target in the treatment of tumors harboring deficiencies in BRCA1/2—mediated homologous recombination (HR), some tumor cells survive, resulting in disease relapse. It has been suggested that alternative RAD52-mediated HR can protect BRCA1/2-deficient cells from the accumulation of DNA damage and the synthetic lethal effect of PARPi. Thus, simultaneous inhibition of RAD52 and PARP1 might result in a robust dual synthetic lethality, effectively eradicating BRCA1/2-deficient tumor cells. In this review, we will discuss the role of RAD52 and its potential application in synthetic lethality-based anticancer therapies.

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A preliminary study on the synthetic lethal effect of berberine and olaparib on pancreatic cancer cells and its mechanism

E3S Web of Conferences ◽

10.1051/e3sconf/202123302023 ◽

2021 ◽

Vol 233 ◽

pp. 02023

Author(s):

Chengyong Zhang ◽

Tingting Yang ◽

Xiaoting Chen ◽

Jiexuan Xu ◽

Danlu Liang ◽

...

Keyword(s):

Pancreatic Cancer ◽

Dna Damage ◽

Cancer Cells ◽

Oxidative Dna Damage ◽

Parp Inhibitor ◽

Cell Activity ◽

Lethal Effect ◽

Synthetic Lethal ◽

Pancreatic Cancer Cells ◽

Apoptosis Inhibitor

Pancreatic cancer is a kind of malignant tumor with high mortality rate. Early operation and late chemoradiotherapy are the treatment criteria, but the prognosis is still poor. Berberine, an alkaloid compound present in many herbal plants, is capable of inducing oxidative DNA damage and downregulating homologous recombination repair (HRR) in cancer cells. Poly (ADP ribose) polymerase-1 (PARP-1) is a sensor of DNA damage with key roles in DNA repair. In this study, we demonstrated that berberine and PARP inhibitor olaparib have a synthetic lethal effect on pancreatic cancer cells. The expression level of RAD51 were reduced by berberine. Correspondingly, PARP became hyperactivated in response to berberine treatment. When berberine is combined with olaparib, the expression of Rad51 and Parp are inhibited. The combination of berberine and olaparib synergistically inhibit cell activity and induce cell apoptosis. In addition, the synergistic effect of berberine and olaparib can be reversed by apoptosis inhibitor and necrosis inhibitor. Together, the results indicate that berberine combined with olaparib have a synthetic lethal effect on pancreatic cancer cells.

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DNA Junction Ligands Trigger DNA Damage and Are Synthetic Lethal with DNA Repair Inhibitors in Cancer Cells

Journal of the American Chemical Society ◽

10.1021/jacs.9b11150 ◽

2019 ◽

Vol 142 (1) ◽

pp. 424-435 ◽

Cited By ~ 5

Author(s):

Katerina Duskova ◽

Pauline Lejault ◽

Élie Benchimol ◽

Régis Guillot ◽

Sébastien Britton ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Cancer Cells ◽

Synthetic Lethal ◽

Dna Repair Inhibitors

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PARP inhibitors in gastric cancer: beacon of hope

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-02005-6 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Yali Wang ◽

Kun Zheng ◽

Yongbiao Huang ◽

Hua Xiong ◽

Jinfang Su ◽

...

Keyword(s):

Gastric Cancer ◽

Dna Damage ◽

Dna Repair ◽

Genome Instability ◽

Parp Inhibitors ◽

Synthetic Lethal ◽

Strand Breaks ◽

Cellular Processes ◽

Single Strand Breaks ◽

Damage Repair

AbstractDefects in the DNA damage response (DDR) can lead to genome instability, producing mutations or aberrations that promote the development and progression of cancer. But it also confers such cells vulnerable to cell death when they inhibit DNA damage repair. Poly (ADP-ribose) polymerase (PARP) plays a central role in many cellular processes, including DNA repair, replication, and transcription. PARP induces the occurrence of poly (ADP-ribosylation) (PARylation) when DNA single strand breaks (SSB) occur. PARP and various proteins can interact directly or indirectly through PARylation to regulate DNA repair. Inhibitors that directly target PARP have been found to block the SSB repair pathway, triggering homologous recombination deficiency (HRD) cancers to form synthetic lethal concepts that represent an anticancer strategy. It has therefore been investigated in many cancer types for more effective anti-cancer strategies, including gastric cancer (GC). This review describes the antitumor mechanisms of PARP inhibitors (PARPis), and the preclinical and clinical progress of PARPis as monotherapy and combination therapy in GC.

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CUT Domain Proteins in DNA Repair and Cancer

Cancers ◽

10.3390/cancers13122953 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2953

Author(s):

Zubaidah M. Ramdzan ◽

Elise Vickridge ◽

Camila C. F. Faraco ◽

Alain Nepveu

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Cancer Cells ◽

Oxidative Dna Damage ◽

Excision Repair ◽

Ras Pathway ◽

Synthetic Lethal ◽

Activating Mutations ◽

Elevated Expression ◽

Base Excision

Recent studies revealed that CUT domains function as accessory factors that accelerate DNA repair by stimulating the enzymatic activities of the base excision repair enzymes OGG1, APE1, and DNA pol β. Strikingly, the role of CUT domain proteins in DNA repair is exploited by cancer cells to facilitate their survival. Cancer cells in which the RAS pathway is activated produce an excess of reactive oxygen species (ROS) which, if not counterbalanced by increased production of antioxidants, causes sustained oxidative DNA damage and, ultimately, cell senescence. These cancer cells can adapt by increasing their capacity to repair oxidative DNA damage in part through elevated expression of CUT domain proteins such as CUX1, CUX2, or SATB1. In particular, CUX1 overexpression was shown to cooperate with RAS in the formation of mammary and lung tumors in mice. Conversely, knockdown of CUX1, CUX2, or SATB1 was found to be synthetic lethal in cancer cells exhibiting high ROS levels as a consequence of activating mutations in KRAS, HRAS, BRAF, or EGFR. Importantly, as a byproduct of their adaptation, cancer cells that overexpress CUT domain proteins exhibit increased resistance to genotoxic treatments such as ionizing radiation, temozolomide, and cisplatin.

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Platinum Complexes in Colorectal Cancer and Other Solid Tumors

Cancers ◽

10.3390/cancers13092073 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2073

Author(s):

Beate Köberle ◽

Sarah Schoch

Keyword(s):

Colorectal Cancer ◽

Dna Damage ◽

Dna Repair ◽

Cancer Cells ◽

Cisplatin Resistance ◽

Platinum Complexes ◽

Dna Lesions ◽

Dna Damage Signaling ◽

Repair Mechanisms ◽

P53 Inactivation

Cisplatin is one of the most commonly used drugs for the treatment of various solid neoplasms, including testicular, lung, ovarian, head and neck, and bladder cancers. Unfortunately, the therapeutic efficacy of cisplatin against colorectal cancer is poor. Various mechanisms appear to contribute to cisplatin resistance in cancer cells, including reduced drug accumulation, enhanced drug detoxification, modulation of DNA repair mechanisms, and finally alterations in cisplatin DNA damage signaling preventing apoptosis in cancer cells. Regarding colorectal cancer, defects in mismatch repair and altered p53-mediated DNA damage signaling are the main factors controlling the resistance phenotype. In particular, p53 inactivation appears to be associated with chemoresistance and poor prognosis. To overcome resistance in cancers, several strategies can be envisaged. Improved cisplatin analogues, which retain activity in resistant cancer, might be applied. Targeting p53-mediated DNA damage signaling provides another therapeutic strategy to circumvent cisplatin resistance. This review provides an overview on the DNA repair pathways involved in the processing of cisplatin damage and will describe signal transduction from cisplatin DNA lesions, with special attention given to colorectal cancer cells. Furthermore, examples for improved platinum compounds and biochemical modulators of cisplatin DNA damage signaling will be presented in the context of colon cancer therapy.

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Monohydrazone Based G-Quadruplex Selective Ligands Induce DNA Damage and Genome Instability in Human Cancer Cells

Journal of Medicinal Chemistry ◽

10.1021/acs.jmedchem.9b01866 ◽

2020 ◽

Vol 63 (6) ◽

pp. 3090-3103 ◽

Cited By ~ 3

Author(s):

Jussara Amato ◽

Giulia Miglietta ◽

Rita Morigi ◽

Nunzia Iaccarino ◽

Alessandra Locatelli ◽

...

Keyword(s):

Dna Damage ◽

Cancer Cells ◽

Genome Instability ◽

Human Cancer ◽

Human Cancer Cells ◽

G Quadruplex ◽

Selective Ligands

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Single-Strand Break End Resection in Genome Integrity: Mechanism and Regulation by APE2

International Journal of Molecular Sciences ◽

10.3390/ijms19082389 ◽

2018 ◽

Vol 19 (8) ◽

pp. 2389 ◽

Cited By ~ 16

Author(s):

Md. Hossain ◽

Yunfeng Lin ◽

Shan Yan

Keyword(s):

Dna Damage ◽

Genome Instability ◽

Strand Break ◽

Single Strand ◽

Genome Integrity ◽

Single Strand Break ◽

Strand Breaks ◽

Single Strand Breaks ◽

Damage Response ◽

End Resection

DNA single-strand breaks (SSBs) occur more than 10,000 times per mammalian cell each day, representing the most common type of DNA damage. Unrepaired SSBs compromise DNA replication and transcription programs, leading to genome instability. Unrepaired SSBs are associated with diseases such as cancer and neurodegenerative disorders. Although canonical SSB repair pathway is activated to repair most SSBs, it remains unclear whether and how unrepaired SSBs are sensed and signaled. In this review, we propose a new concept of SSB end resection for genome integrity. We propose a four-step mechanism of SSB end resection: SSB end sensing and processing, as well as initiation, continuation, and termination of SSB end resection. We also compare different mechanisms of SSB end resection and DSB end resection in DNA repair and DNA damage response (DDR) pathways. We further discuss how SSB end resection contributes to SSB signaling and repair. We focus on the mechanism and regulation by APE2 in SSB end resection in genome integrity. Finally, we identify areas of future study that may help us gain further mechanistic insight into the process of SSB end resection. Overall, this review provides the first comprehensive perspective on SSB end resection in genome integrity.

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Motor Coordination in Space: An Analysis of the Effects of Microgravity on XRCCI DNA Repair Protein Function

10.21203/rs.3.pex-1267/v1 ◽

2020 ◽

Author(s):

Vishruth Nagam

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Protein Function ◽

Motor Coordination ◽

Strand Break ◽

Single Strand Break ◽

Single Strand Break Repair ◽

Repair Protein ◽

Mature Neurons ◽

Microgravity Conditions

Abstract While in space, astronauts have been known to face exposure to stressors that may increase susceptibility to DNA damage. If DNA repair proteins are defective or nonexistent, DNA mutations may accumulate, causing increasingly abnormal function as one ages [1]. The DNA single-strand break repair protein XRCC1 is important for cerebellar neurogenesis and interneuron development [2]. According to previous studies, a deficiency of XRCC1 can lead to an increase in DNA damage, in mature neurons, and ataxia (a progressive loss of motor coordination) [2]. I propose to address how XRCC1’s efficiency can change in microgravity conditions. This experiment’s relevance is underscored by the importance of motor coordination and physical fitness for astronauts; determining the potential effects of microgravity on XRCC1 is crucial for future space exploration.

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WIP1 Promotes Homologous Recombination and Modulates Sensitivity to PARP Inhibitors

Cells ◽

10.3390/cells8101258 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1258 ◽

Cited By ~ 5

Author(s):

Kamila Burdova ◽

Radka Storchova ◽

Matous Palek ◽

Libor Macurek

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Homologous Recombination ◽

Cancer Cells ◽

Genotoxic Stress ◽

Parp Inhibitors ◽

Cell Cycle Checkpoint ◽

Dna Lesion ◽

Cycle Checkpoint ◽

G2 Cells

Genotoxic stress triggers a combined action of DNA repair and cell cycle checkpoint pathways. Protein phosphatase 2C delta (referred to as WIP1) is involved in timely inactivation of DNA damage response by suppressing function of p53 and other targets at chromatin. Here we show that WIP1 promotes DNA repair through homologous recombination. Loss or inhibition of WIP1 delayed disappearance of the ionizing radiation-induced 53BP1 foci in S/G2 cells and promoted cell death. We identify breast cancer associated protein 1 (BRCA1) as interactor and substrate of WIP1 and demonstrate that WIP1 activity is needed for correct dynamics of BRCA1 recruitment to chromatin flanking the DNA lesion. In addition, WIP1 dephosphorylates 53BP1 at Threonine 543 that was previously implicated in mediating interaction with RIF1. Finally, we report that inhibition of WIP1 allowed accumulation of DNA damage in S/G2 cells and increased sensitivity of cancer cells to a poly-(ADP-ribose) polymerase inhibitor olaparib. We propose that inhibition of WIP1 may increase sensitivity of BRCA1-proficient cancer cells to olaparib.

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