PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance

Rose, Maddison; Burgess, Joshua T.; O’Byrne, Kenneth J.; Richard, Derek J.; Bolderson, Emma

doi:10.3389/fcell.2020.564601

Cited by 346 publications

(264 citation statements)

References 261 publications

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“…DNA repair-based targeted therapy for breast cancer induces cell death through impairing DNA repair pathways and increasing the accumulation of DNA damage and breaks. Targeted therapy has less off-target side effects and greater sensitivity than chemotherapy and radiation [ 116 ]. Some of our DEGs are known to be very important drug targets for breast cancer patients.…”

Section: Discussionmentioning

confidence: 99%

The overexpression of DNA repair genes in invasive ductal and lobular breast carcinomas: Insights on individual variations and precision medicine

et al. 2021

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In the era of precision medicine, analyzing the transcriptomic profile of patients is essential to tailor the appropriate therapy. In this study, we explored transcriptional differences between two invasive breast cancer subtypes; infiltrating ductal carcinoma (IDC) and lobular carcinoma (LC) using RNA-Seq data deposited in the TCGA-BRCA project. We revealed 3854 differentially expressed genes between normal ductal tissues and IDC. In addition, IDC to LC comparison resulted in 663 differentially expressed genes. We then focused on DNA repair genes because of their known effects on patients’ response to therapy and resistance. We here report that 36 DNA repair genes are overexpressed in a significant number of both IDC and LC patients’ samples. Despite the upregulation in a significant number of samples, we observed a noticeable variation in the expression levels of the repair genes across patients of the same cancer subtype. The same trend is valid for the expression of miRNAs, where remarkable variations between patients’ samples of the same cancer subtype are also observed. These individual variations could lie behind the differential response of patients to treatment. The future of cancer diagnostics and therapy will inevitably depend on high-throughput genomic and transcriptomic data analysis. However, we propose that performing analysis on individual patients rather than a big set of patients’ samples will be necessary to ensure that the best treatment is determined, and therapy resistance is reduced.

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Section: Discussionmentioning

confidence: 99%

The overexpression of DNA repair genes in invasive ductal and lobular breast carcinomas: Insights on individual variations and precision medicine

et al. 2021

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“…In the past decade, PARP inhibitors have made their way from the lab to the clinic, with demonstrated therapeutic benefits [ 91 ]. So far, clinical benefit of PARP inhibitors in cancer treatment has been limited to inhibitors of nuclear PARPs (e.g., PARP-1) [ 91 ]. As discussed above, MARTs are exciting therapeutic targets for several diseases, but the development of clinical inhibitors of these MARTs has lagged behind.…”

Section: Development Of Mart Inhibitorsmentioning

confidence: 99%

“…As discussed above, MARTs are exciting therapeutic targets for several diseases, but the development of clinical inhibitors of these MARTs has lagged behind. However, recent advances in the understanding of MART structure and catalytic activity, as well as the ability to detect MARylation, has led to significant progress in developing MART inhibitors [ 4 , 91 ]. In many cases, auto-modification of the MART is used as readout for catalytic activity.…”

Section: Development Of Mart Inhibitorsmentioning

confidence: 99%

MARTs and MARylation in the Cytosol: Biological Functions, Mechanisms of Action, and Therapeutic Potential

Challa

Stokes

Kraus

2021

Cells

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Mono(ADP-ribosyl)ation (MARylation) is a regulatory post-translational modification of proteins that controls their functions through a variety of mechanisms. MARylation is catalyzed by mono(ADP-ribosyl) transferase (MART) enzymes, a subclass of the poly(ADP-ribosyl) polymerase (PARP) family of enzymes. Although the role of PARPs and poly(ADP-ribosyl)ation (PARylation) in cellular pathways, such as DNA repair and transcription, is well studied, the role of MARylation and MARTs (i.e., the PARP ‘monoenzymes’) are not well understood. Moreover, compared to PARPs, the development of MART-targeted therapeutics is in its infancy. Recent studies are beginning to shed light on the structural features, catalytic targets, and biological functions of MARTs. The development of new technologies to study MARTs have uncovered essential roles for these enzymes in the regulation of cellular processes, such as RNA metabolism, cellular transport, focal adhesion, and stress responses. These insights have increased our understanding of the biological functions of MARTs in cancers, neuronal development, and immune responses. Furthermore, several novel inhibitors of MARTs have been developed and are nearing clinical utility. In this review, we summarize the biological functions and molecular mechanisms of MARTs and MARylation, as well as recent advances in technology that have enabled detection and inhibition of their activity. We emphasize PARP-7, which is at the forefront of the MART subfamily with respect to understanding its biological roles and the development of therapeutically useful inhibitors. Collectively, the available studies reveal a growing understanding of the biochemistry, chemical biology, physiology, and pathology of MARTs.

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“…Given that hypoxia induces mutations in DNA repair genes and downregulates DNA repair pathways, hypoxic tumors can be alternatively targeted by synthetic lethality and contextual lethality, respectively. Tumors with mutated HR genes, BRCA1 and BRCA2, harbor lower HRR capacity and are more sensitive to Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi), resulting in synthetic lethality ( Rose et al, 2020 ). Since tumor hypoxia induces mutations in HRR genes, hypoxic cancer cells may be synthetically targeted by PARPi.…”

Section: Targeting Tumor Hypoxia and Future Directionsmentioning

confidence: 99%

Tumor Hypoxia Drives Genomic Instability

Tang

Bolderson

O’Byrne

et al. 2021

Front. Cell Dev. Biol.

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Cancer is a leading cause of death worldwide. As a common characteristic of cancer, hypoxia is associated with poor prognosis due to enhanced tumor malignancy and therapeutic resistance. The enhanced tumor aggressiveness stems at least partially from hypoxia-induced genomic instability. Therefore, a clear understanding of how tumor hypoxia induces genomic instability is crucial for the improvement of cancer therapeutics. This review summarizes recent developments highlighting the association of tumor hypoxia with genomic instability and the mechanisms by which tumor hypoxia drives genomic instability, followed by how hypoxic tumors can be specifically targeted to maximize efficacy.

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PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance

Cited by 346 publications

References 261 publications

The overexpression of DNA repair genes in invasive ductal and lobular breast carcinomas: Insights on individual variations and precision medicine

The overexpression of DNA repair genes in invasive ductal and lobular breast carcinomas: Insights on individual variations and precision medicine

MARTs and MARylation in the Cytosol: Biological Functions, Mechanisms of Action, and Therapeutic Potential

Tumor Hypoxia Drives Genomic Instability

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