The Multifactorial Role of PARP-1 in Tumor Microenvironment

Martí, Juan Manuel; Fernández-Cortés, Mónica; Serrano-Sáenz, Santiago; Zamudio-Martínez, Esteban; Delgado-Bellido, Daniel; García-Díaz, Ángel; Oliver, F. Javier

doi:10.3390/cancers12030739

Cited by 36 publications

(43 citation statements)

References 152 publications

(173 reference statements)

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“…Therefore, targeting DNA repair-associated proteins is increasingly becoming an applicable approach to cancer treatment. Single-strand breaks (SSBs) can be accurately repaired using the other strand as a template, and this process involves the poly (ADP-ribose) polymerase (PARP) enzyme [ 6 ]. DNA double-strand breaks (DSBs) are repaired through two pathways: the HR pathway and non-homologous end joining, although other mechanisms also exist [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

PARP Inhibition Increases the Reliance on ATR/CHK1 Checkpoint Signaling Leading to Synthetic Lethality—An Alternative Treatment Strategy for Epithelial Ovarian Cancer Cells Independent from HR Effectiveness

Gralewska

Gajek

Marczak

et al. 2020

IJMS

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Poly (ADP-ribose) polymerase inhibitor (PARPi, olaparib) impairs the repair of DNA single-strand breaks (SSBs), resulting in double-strand breaks (DSBs) that cannot be repaired efficiently in homologous recombination repair (HRR)-deficient cancers such as BRCA1/2-mutant cancers, leading to synthetic lethality. Despite the efficacy of olaparib in the treatment of BRCA1/2 deficient tumors, PARPi resistance is common. We hypothesized that the combination of olaparib with anticancer agents that disrupt HRR by targeting ataxia telangiectasia and Rad3-related protein (ATR) or checkpoint kinase 1 (CHK1) may be an effective strategy to reverse ovarian cancer resistance to olaparib. Here, we evaluated the effect of olaparib, the ATR inhibitor AZD6738, and the CHK1 inhibitor MK8776 alone and in combination on cell survival, colony formation, replication stress response (RSR) protein expression, DNA damage, and apoptotic changes in BRCA2 mutated (PEO-1) and HRR-proficient BRCA wild-type (SKOV-3 and OV-90) cells. Combined treatment caused the accumulation of DNA DSBs. PARP expression was associated with sensitivity to olaparib or inhibitors of RSR. Synergistic effects were weaker when olaparib was combined with CHK1i and occurred regardless of the BRCA2 status of tumor cells. Because PARPi increases the reliance on ATR/CHK1 for genome stability, the combination of PARPi with ATR inhibition suppressed ovarian cancer cell growth independently of the efficacy of HRR. The present results were obtained at sub-lethal doses, suggesting the potential of these inhibitors as monotherapy as well as in combination with olaparib.

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Section: Introductionmentioning

confidence: 99%

PARP Inhibition Increases the Reliance on ATR/CHK1 Checkpoint Signaling Leading to Synthetic Lethality—An Alternative Treatment Strategy for Epithelial Ovarian Cancer Cells Independent from HR Effectiveness

Gralewska

Gajek

Marczak

et al. 2020

IJMS

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“…To this end, several assays have been developed to detect HR functional state scoring, with some promising results [28,29]. Nevertheless, PARPs are pleiotropic enzymes with functions that exceed the well-known DNA repair, and may impact in the tumor microenvironment, having a therapeutic value beyond cell-autonomous synthetic lethality [34].…”

Section: Discussionmentioning

confidence: 99%

“…PARPs are pleiotropic molecules that play a role in different mechanisms associated with both pro-and anti-angiogenic effects [34]. Several reports have highlighted the role of PARP-1 in angiogenesis.…”

Section: Olaparib Can Inhibit Angiogenesis or Normalize Tumor Vesselsmentioning

confidence: 99%

“…This model represents not only a feasible clinical platform for therapy screening for personalized treatments within the clinical decision timeframe, but also a valuable tool to study the interlink between tumor microenvironment and therapeutic response [32,33]. This is particularly important in PARPi therapies, since a plethora of different roles for PARP proteins have been described, from their role in DDR to functions related to the TME, such as angiogenesis, epithelial to mesenchymal transition (EMT) (involved in the metastatic process), or the interplay with the immune system [34][35][36]. Therefore, a model that can go beyond the cell's intrinsic responses can be of great value.…”

Section: Introductionmentioning

confidence: 99%

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Zebrafish Xenografts Unveil Sensitivity to Olaparib beyond BRCA Status

Varanda

Martins-Logrado

Ferreira

et al. 2020

Cancers

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Poly (ADP-ribose) polymerase (PARP) inhibition in BRCA-mutated cells results in an incapacity to repair DNA damage, leading to cell death caused by synthetic lethality. Within the treatment options for advanced triple negative breast cancer, the PARP inhibitor olaparib is only given to patients with BRCA1/2 mutations. However, these patients may show resistance to this drug and BRCA1/2 wild-type tumors can show a striking sensitivity, making BRCA status a poor biomarker for treatment choice. Aiming to investigate if the zebrafish model can discriminate sensitivities to olaparib, we developed zebrafish xenografts with different BRCA status and measured tumor response to treatment, as well as its impact on angiogenesis and metastasis. When challenged with olaparib, xenografts revealed sensitivity phenotypes independent of BRCA. Moreover, its combination with ionizing radiation increased the cytotoxic effects, showing potential as a combinatorial regimen. In conclusion, we show that the zebrafish xenograft model may be used as a sensitivity profiling platform for olaparib in monotherapy or in combinatorial regimens. Hence, this model presents as a promising option for the future establishment of patient-derived xenografts for personalized medicine approaches beyond BRCA status.

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“…PARP1 deficiency in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model led to the development of less differentiated tumours with a higher proliferative index compared to wild-type rodents. The driving mechanism involved TGF-β (transforming growth factor β)-dependent and Smad-regulated epithelial-mesenchymal transition [ 35 , 38 ]. PARP modulates the development and growth of cancer by altering cancer-initiating cells, the immune response, angiogenesis, autophagy and the tumour hypoxic response.…”

Section: Role Of Parp In Prostate Cancer (Pca) Biologymentioning

confidence: 99%

Poly(ADP-Ribose) Polymerase Inhibitors in Prostate Cancer: Molecular Mechanisms, and Preclinical and Clinical Data

2020

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Genomic instability is one of the hallmarks of cancer. The incidence of genetic alterations in homologous recombination repair genes increases during cancer progression, and 20% of prostate cancers (PCas) have defects in DNA repair genes. Several somatic and germline gene alterations drive prostate cancer tumorigenesis, and the most important of these are BRCA2, BRCA1, ATM and CHEK2. There is a group of BRCAness tumours that share phenotypic and genotypic properties with classical BRCA-mutated tumours. Poly(ADP-ribose) polymerase inhibitors (PARPis) show synthetic lethality in cancer cells with impaired homologous recombination genes, and patients with these alterations are candidates for PARPi therapy. Androgen deprivation therapy is the mainstay of PCa therapy. PARPis decrease androgen signalling by interaction with molecular mechanisms of the androgen nuclear complex. The PROFOUND phase III trial, comparing olaparib with enzalutamide/abiraterone therapy, revealed increased radiological progression-free survival (rPFS) and overall survival (OS) among patients with metastatic castration-resistant prostate cancer (mCRPC) with BRCA1, BRCA2 or ATM mutations. The clinical efficacy of PARPis has been confirmed in ovarian, breast, pancreatic and recently also in a subset of PCa. There is growing evidence that molecular tumour boards are the future of the oncological therapeutic approach in prostate cancer. In this review, we summarise the data concerning the molecular mechanisms and preclinical and clinical data of PARPis in PCa. Key Points Molecular tumour profiling is a new approach for personalised targeted therapy in cancer patients.

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The Multifactorial Role of PARP-1 in Tumor Microenvironment

Cited by 36 publications

References 152 publications

PARP Inhibition Increases the Reliance on ATR/CHK1 Checkpoint Signaling Leading to Synthetic Lethality—An Alternative Treatment Strategy for Epithelial Ovarian Cancer Cells Independent from HR Effectiveness

PARP Inhibition Increases the Reliance on ATR/CHK1 Checkpoint Signaling Leading to Synthetic Lethality—An Alternative Treatment Strategy for Epithelial Ovarian Cancer Cells Independent from HR Effectiveness

Zebrafish Xenografts Unveil Sensitivity to Olaparib beyond BRCA Status

Poly(ADP-Ribose) Polymerase Inhibitors in Prostate Cancer: Molecular Mechanisms, and Preclinical and Clinical Data

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