Efficacy and safety of PARP inhibitors in the treatment of prostatic cancer: a systematic review and network meta-analysis.

BACKGROUND: Prostate cancer (PCa) is the most common cancer and the second leading cause of cancer-related death in men. Previous studies have shown that the poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors (PARPis) improve the treatment response of patients with metastatic castration-resistant PCa (mCRPC). However, the efficacy and safety of various PARPis in mCRPC patients remain unclear, presenting a significant challenge for clinicians when making treatment decisions. To address this, this study conducted two indirect comparisons to evaluate the efficacy and safety of four PARPis (olaparib, niraparib, rucaparib, and talazoparib) in patients with mCRPC. METHODS: A systematic review and network meta-analysis (NMA) using Bayesian statistics was conducted. A comprehensive literature search was performed of the PubMed, Web of Science, Cochrane Library, Embase, and China National Knowledge Infrastructure (CNKI) databases to identify relevant studies from the inception to November 8, 2023, using search terms such as "PARP inhibitor", "olaparib", "rucaparib", "niraparib", "talazoparib", and "mCRPC". Phase 2/3 randomized controlled trials (RCTs) related to PARPi therapy and novel hormonal therapy in patients with mCRPC were included in the analysis. The targeted outcomes included radiographic progression-free survival (rPFS), overall survival (OS), adverse events (AEs), and grade ≥3 AEs. Four reviewers screened the titles and abstracts independently to assess the eligibility of each article. Two researchers independently extracted data from the included studies. The risk of bias and quality of the studies were assessed using the Risk-of-Bias 2 tool. RESULTS: Six high-quality phase 2/3 clinical trials, comprising 3,205 individuals, were selected for the systematic review and NMAs. Two NMAs were conducted due to the different designs of the six clinical trials. The indirect comparison with a random-effects model of olaparib, niraparib, and talazoparib showed that olaparib significantly improved rPFS with a hazard ratio (HR) of 0.67 [95% confidence interval (CI): 0.46-0.96]; however, no such significant difference was observed in relation to olaparib and rucaparib. In terms of OS, no significant difference was observed among olaparib, niraparib, and talazoparib. In relation to the AEs, the PARPi interventions using olaparib, niraparib, and talazoparib increased the rates of grade ≥3 AEs with odds ratios (ORs) of 2.0 (95% CI: 0.89-5.3), 3.0 (95% CI: 1.3-7.4), and 3.7 (95% CI: 1.1-12.0), respectively. In the rank probability analysis, according to the surface under the cumulative ranking (SUCRA), olaparib ranked first, followed by niraparib, and talazoparib. Most of the included studies were assessed to be at low risk of bias. CONCLUSIONS: Olaparib significantly improved rPFS among olaparib, niraparib, and talazoparib. Talazoparib exhibited the highest SUCRA value. Regarding safety, olaparib and rucaparib did not significantly increase the incidence of grade ≥3 AEs. When making personalized treatment decisions, clinicians should consider individual patient characteristics, treatment efficacy, and potential AEs.

Harnessing immune cells to leverage PARP inhibitors.

Homologous-recombination deficiency in DNA repair characterizes a unique group of cancers that are vulnerable to PARP inhibitors and cytotoxic chemotherapy. In this issue of Cell, Luo et al., demonstrated that this genetic attribute in cancer cells may reprogram tumor immune microenvironment and show promise of targeting effector-Treg cells.

Iron: The Secret Ingredient Breaking PARPi Resistance.

PARP inhibitors (PARPi) are used as a first-line treatment option for cancers with BRCA1/2 mutations, yet a significant number of patients show a limited response to these agents. In the present study, Lei and colleagues demonstrate that PARPi promote increased ferroptosis sensitivity and this can be exploited therapeutically to improve the response to PARPi, marking an important therapeutic concept to exploit ferroptosis-based strategies in clinical settings. See related article by Lei et al., p. 1476 (2).

Mechanism and rational combinations with GP-2250, a novel oxathiazine derivative, in ovarian cancer.

BACKGROUND: GP-2250, a novel analog of taurultam (TRLT), has emerged as a potent anti-neoplastic drug; however, the mechanisms underlying its effects are not well understood. Here, we investigated the mechanism of action and the biological effects of GP-2250 using in vitro and in vivo models. METHODS: We carried out a series of in vitro (MTT assay, Annexin V/PI assay, colony formation assay, reverse-phase protein array [RPPA], and HRLC/IC analysis) to determine the biological activity of GP-2250 and investigate the mechanism of action. In vivo experiments were carried out to determine the therapeutic efficacy of GP-2250 alone and in combination with standard-of-care drugs (e.g., paclitaxel, cisplatin, topotecan, and poly ADP-ribose polymerase [PARP] inhibitors). RESULTS: We investigated the cytotoxic effect of GP-2250 in 10 ovarian cancer cell lines and found GP-2250 combined with a PARP inhibitor had the greatest synergy. RPPA revealed that GP-2250 inhibited hypoxia-inducible factor-1α, AKT, and mammalian target of rapamycin (mTOR) activation and expression. High-resolution mass spectrometry revealed that hexokinase2 activity and protein expression were significantly reduced by GP-2250 exposure. Furthermore, GP-2250 reduced glycolysis and ATP synthesis in cancer cells. An in vivo pharmacodynamic experiment using the OVCAR8 mouse model demonstrated that 500 mg/kg GP-2250 was effective in downregulating AKT and mTOR activation and expression. In the in vivo therapy experiment using an orthotopic mouse model, a combination of GP-2250 with either PARP inhibitors or bevacizumab showed a significant reduction of tumor weights and nodules compared to those treated with a vehicle, control IgG groups, or monotherapy groups. CONCLUSIONS: Taken together, our data indicate that GP-2250 exerts profound effects on tumor metabolism and, in combination with PARP inhibitors or bevacizumab, showed promising anti-tumor efficacy. These findings could have implications for the clinical development of GP-2250.

Histone-methyltransferase KMT2D deficiency impairs the Fanconi anemia/BRCA pathway upon glycolytic inhibition in squamous cell carcinoma.

Histone lysine methyltransferase 2D (KMT2D) is the most frequently mutated epigenetic modifier in head and neck squamous cell carcinoma (HNSCC). However, the role of KMT2D in HNSCC tumorigenesis and whether its mutations confer any therapeutic vulnerabilities remain unknown. Here we show that KMT2D deficiency promotes HNSCC growth through increasing glycolysis. Additionally, KMT2D loss decreases the expression of Fanconi Anemia (FA)/BRCA pathway genes under glycolytic inhibition. Mechanistically, glycolytic inhibition facilitates the occupancy of KMT2D to the promoter/enhancer regions of FA genes. KMT2D loss reprograms the epigenomic landscapes of FA genes by transiting their promoter/enhancer states from active to inactive under glycolytic inhibition. Therefore, combining the glycolysis inhibitor 2-DG with DNA crosslinking agents or poly (ADP-ribose) polymerase (PARP) inhibitors preferentially inhibits tumor growth of KMT2D-deficient mouse HNSCC and patient-derived xenografts (PDXs) harboring KMT2D-inactivating mutations. These findings provide an epigenomic basis for developing targeted therapies for HNSCC patients with KMT2D-inactivating mutations.

Endogenous base damage as a driver of genomic instability in homologous recombination-deficient cancers.

Homologous recombination (HR) is a high-fidelity DNA double-strand break (DSB) repair pathway. Both familial and somatic loss of function mutation(s) in various HR genes predispose to a variety of cancer types, underscoring the importance of error-free repair of DSBs in human physiology. While environmental sources of DSBs have been known, more recent studies have begun to uncover the role of endogenous base damage in leading to these breaks. Base damage repair intermediates often consist of single-strand breaks, which if left unrepaired, can lead to DSBs as the replication fork encounters these lesions. This review summarizes various sources of endogenous base damage and how these lesions are repaired. We highlight how conversion of base repair intermediates, particularly those with 5'or 3' blocked ends, to DSBs can be a predominant source of genomic instability in HR-deficient cancers. We also discuss how endogenous base damage and ensuing DSBs can be exploited to enhance the efficacy of Poly (ADP-ribose) polymerase inhibitors (PARPi), that are widely used in the clinics for the regimen of HR-deficient cancers.

Salicylaldehyde-derived piperazine-functionalized hydrazone ligand-based Pt(II) complexes: inhibition of EZH2-dependent tumorigenesis in pancreatic ductal adenocarcinoma, synergism with PARP inhibitors and enhanced apoptosis.

Piperazine is an important functional unit of many clinically approved drugs, including chemotherapeutic agents. In the current study, methyl piperazine was incorporated and eight salicylaldehyde-derived piperazine-functionalized hydrazone ONN-donor ligands (L) and their Pt(II) complexes (L-PtCl) were prepared. The structures of all these ligands (L1-L8) and Pt(II) complexes (C1-C8) were determined using 1H and 13C NMR, UV-vis, FT-IR and HR-ESI MS analyses, whereas the structures of C1, C5, C6, C7 and C8 were determined in the solid state using single crystal X-ray diffraction analysis. Solution state stabilities of C3, C4, C5 and C6 were determined via time-dependent UV-vis spectroscopy. All these complexes (C1-C8) were studied for their anticancer effect in pancreatic ductal adenocarcinoma cells, including BxPC3, MIAPaCa-2 and PANC1 cells. C1-C8 displayed a potential cytotoxic effect in all these cancer cells, among which C5, C6 and C8 showed the strongest inhibitory effect in comparison with standard chemotherapeutic agents, including 5-fluorouracil (5-FU), cisplatin (CP), oxaliplatin and doxorubicin (DOX). C5, C6 and C8 suppressed the growth of pancreatic cancer cells in a dose-dependent manner. Moreover, C5, C6 and C8 inhibited clonogenic potential and invasion ability and induced apoptosis in PANC1 cells. Importantly, C5, C6 and C8 synergized the anticancer effect with PARP inhibitors, including olaparib, veliparib and niraparib, in pancreatic cancer cells, thus suggesting an important role of C5, C6 and C8 in induction of apoptosis in combination with PARP inhibitors. C5 combined with PARP inhibitors induced caspase3/7 activity and suppressed ATP production. Mechanistically, C5, C6 and C8 inhibited EZH2 protein expression to suppress EZH2-dependent tumorigenesis. Overall, these results highlighted the importance of these piperazine-functionalized Pt(II) complexes as potential anticancer agents to suppress pancreatic ductal adenocarcinoma tumorigenesis by targeting the EZH2-dependent pathway.

Targeted Nanocarrier-Based Drug Delivery Strategies for Improving the Therapeutic Efficacy of PARP Inhibitors against Ovarian Cancer.

The current focus of ovarian cancer (OC) research is the improvement of treatment options through maximising drug effectiveness. OC remains the fifth leading cause of cancer-induced mortality in women worldwide. In recent years, nanotechnology has revolutionised drug delivery systems. Nanoparticles may be utilised as carriers in gene therapy or to overcome the problem of drug resistance in tumours by limiting the number of free drugs in circulation and thereby minimising undesired adverse effects. Cell surface receptors, such as human epidermal growth factor 2 (HER2), folic acid (FA) receptors, CD44 (also referred to as homing cell adhesion molecule, HCAM), and vascular endothelial growth factor (VEGF) are highly expressed in ovarian cancer cells. Generation of active targeting nanoparticles involves modification with ligands that recognise cell surface receptors and thereby promote internalisation by cancer cells. Several poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are currently used for the treatment of high-grade serous ovarian carcinomas (HGSOC) or platinum-sensitive relapsed OC. However, PARP resistance and poor drug bioavailability are common challenges, highlighting the urgent need to develop novel, effective strategies for ovarian cancer treatment. This review evaluates the utility of nanoparticles in ovarian cancer therapy, with a specific focus on targeted approaches and the use of PARPi nanocarriers to optimise treatment outcomes.

BRCA1 secondary splice-site mutations drive exon-skipping and PARP inhibitor resistance.

PARP inhibitor (PARPi) therapy has transformed outcomes for patients with homologous recombination DNA repair (HRR) deficient ovarian cancers, for example those with BRCA1 or BRCA2 gene defects. Unfortunately, PARPi resistance is common. Multiple resistance mechanisms have been described, including secondary mutations that restore the HR gene reading frame. BRCA1 splice isoforms △11 and △11q can contribute to PARPi resistance by splicing out the mutation-containing exon, producing truncated, partially functional proteins. However, the clinical impacts and underlying drivers of BRCA1 exon skipping are not fully understood.We analyzed nine ovarian and breast cancer patient derived xenografts (PDX) with BRCA1 exon 11 frameshift mutations for exon skipping and therapy response, including a matched PDX pair derived from a patient pre- and post-chemotherapy/PARPi. BRCA1 exon 11 skipping was elevated in PARPi resistant PDX tumors. Two independent PDX models acquired secondary BRCA1 splice site mutations (SSMs) that drive exon skipping, confirmed using qRT-PCR, RNA sequencing, immunoblotting and minigene modelling. CRISPR/Cas9-mediated disruption of splicing functionally validated exon skipping as a mechanism of PARPi resistance. SSMs were also enriched in post-PARPi ovarian cancer patient cohorts from the ARIEL2 and ARIEL4 clinical trials.Few PARPi resistance mechanisms have been confirmed in the clinical setting. While secondary/reversion mutations typically restore a gene's reading frame, we have identified secondary mutations in patient cohorts that hijack splice sites to enhance mutation-containing exon skipping, resulting in the overexpression of BRCA1 hypomorphs, which in turn promote PARPi resistance. Thus, BRCA1 SSMs can and should be clinically monitored, along with frame-restoring secondary mutations.

DNA polymerase α-primase facilitates PARP inhibitor-induced fork acceleration and protects BRCA1-deficient cells against ssDNA gaps.

PARP inhibitors (PARPi), known for their ability to induce replication gaps and accelerate replication forks, have become potent agents in anticancer therapy. However, the molecular mechanism underlying PARPi-induced fork acceleration has remained elusive. Here, we show that the first PARPi-induced effect on DNA replication is an increased replication fork rate, followed by a secondary reduction in origin activity. Through the systematic knockdown of human DNA polymerases, we identify POLA1 as mediator of PARPi-induced fork acceleration. This acceleration depends on both DNA polymerase α and primase activities. Additionally, the depletion of POLA1 increases the accumulation of replication gaps induced by PARP inhibition, sensitizing cells to PARPi. BRCA1-depleted cells are especially susceptible to the formation of replication gaps under POLA1 inhibition. Accordingly, BRCA1 deficiency sensitizes cells to POLA1 inhibition. Thus, our findings establish the POLA complex as important player in PARPi-induced fork acceleration and provide evidence that lagging strand synthesis represents a targetable vulnerability in BRCA1-deficient cells.

Co-Targeting of DTYMK and PARP1 as a Potential Therapeutic Approach in Uveal Melanoma.

Uveal melanoma (UM) is the most common primary intraocular tumor in adults, with no standardized treatment for advanced disease. Based on preliminary bioinformatical analyses DTYMK and PARP1 were selected as potential therapeutic targets. High levels of both proteins were detected in uveal melanoma cells and correlated with increased tumor growth and poor prognosis. In vitro tests on MP41 (BAP1 positive) and MP46 (BAP1 negative) cancer cell lines using inhibitors pamiparib (PARP1) and Ymu1 (DTYMK) demonstrated significant cytotoxic effects. Combined treatment had synergistic effects in MP41 and additive in MP46 cell lines, reducing cell proliferation and inhibiting the mTOR signaling pathway. Furthermore, the applied inhibitors in combination decreased cell motility and migration speed, especially for BAP1-negative cell lines. Our hypothesis of the double hit into tumoral DNA metabolism as a possible therapeutic option in uveal melanoma was confirmed since combined targeting of DTYMK and PARP1 affected all tested cytophysiological parameters with the highest efficiency. Our in vitro findings provide insights into novel therapeutic avenues for managing uveal melanoma, warranting further exploration in preclinical and clinical settings.

Carbamoylation at C-8 position of natural 3-arylcoumarin scaffold for the discovery of novel PARP-1 inhibitors with potent anticancer activity.

Structural modification based on natural privileged scaffolds has proven to be an attractive approach to generate potential antitumor candidates with high potency and specific targeting. As a continuation of our efforts to identify potent PARP-1 inhibitors, natural 3-arylcoumarin scaffold was served as the starting point for the construction of novel structural unit for PARP-1 inhibition. Herein, a series of novel 8-carbamyl-3-arylcoumarin derivatives were designed and synthesized. The antiproliferative activities of target compounds against four BRCA-mutated cancer cells (SUM149PT, HCC1937, MDA-MB-436 and Capan-1) were evaluated. Among them, compound 9b exhibited excellent antiproliferative effects against SUM149PT, HCC1937 and Capan-1 cells with IC50 values of 0.62, 1.91 and 4.26 µM, respectively. Moreover, 9b could significantly inhibit the intracellular PARP-1/2 activity in SUM149PT cells with IC50 values of 2.53 nM and 6.45 nM, respectively. Further mechanism studies revealed that 9b could aggravate DNA double-strand breaks, increase ROS production, decrease mitochondrial membrane potential, arrest cell cycle at G2/M phase and ultimately induce apoptosis in SUM149PT cells. In addition, molecular docking study demonstrated that the binding mode of 9b with PARP-1 was similar to that of niraparib, forming multiple hydrogen bond interactions with the active site of PARP-1. Taken together, these findings suggest that 8-carbamyl-3-arylcoumarin scaffold could serve as an effective structural unit for PARP-1 inhibition and offer a valuable paradigm for the structural modification of natural products.

Leveraging PARP-1/2 to Target Distant Metastasis.

Poly (ADP-Ribose) Polymerase (PARP) inhibitors have changed the outcomes and therapeutic strategy for several cancer types. As a targeted therapeutic mainly for patients with BRCA1/2 mutations, PARP inhibitors have commonly been exploited for their capacity to prevent DNA repair. In this review, we discuss the multifaceted roles of PARP-1 and PARP-2 beyond DNA repair, including the impact of PARP-1 on chemokine signalling, immune modulation, and transcriptional regulation of gene expression, particularly in the contexts of angiogenesis and epithelial-to-mesenchymal transition (EMT). We evaluate the pre-clinical role of PARP inhibitors, either as single-agent or combination therapies, to block the metastatic process. Efficacy of PARP inhibitors was demonstrated via DNA repair-dependent and independent mechanisms, including DNA damage, cell migration, invasion, initial colonization at the metastatic site, osteoclastogenesis, and micrometastasis formation. Finally, we summarize the recent clinical advancements of PARP inhibitors in the prevention and progression of distant metastases, with a particular focus on specific metastatic sites and PARP-1 selective inhibitors. Overall, PARP inhibitors have demonstrated great potential in inhibiting the metastatic process, pointing the way for greater use in early cancer settings.

DNA damage induced PARP-1 overactivation confers paclitaxel-induced neuropathic pain by regulating mitochondrial oxidative metabolism.

AIMS: Poly (ADP-ribose) polymerase (PARP) has been extensively investigated in human cancers. Recent studies verified that current available PARP inhibitors (Olaparib or Veliparib) provided clinical palliation of clinical patients suffering from paclitaxel-induced neuropathic pain (PINP). However, the underlying mechanism of PARP overactivation in the development of PINP remains to be investigated. METHODS AND RESULTS: We reported induction of DNA oxidative damage, PARP-1 overactivation, and subsequent nicotinamide adenine dinucleotide (NAD+) depletion as crucial events in the pathogenesis of PINP. Therefore, we developed an Olaparib PROTAC to achieve the efficient degradation of PARP. Continuous intrathecal injection of Olaparib PROTAC protected against PINP by inhibiting the activity of PARP-1 in rats. PARP-1, but not PARP-2, was shown to be a crucial enzyme in the development of PINP. Specific inhibition of PARP-1 enhanced mitochondrial redox metabolism partly by upregulating the expression and deacetylase activity of sirtuin-3 (SIRT3) in the dorsal root ganglions and spinal cord in the PINP rats. Moreover, an increase in the NAD+ level was found to be a crucial mechanism by which PARP-1 inhibition enhanced SIRT3 activity. CONCLUSION: The findings provide a novel insight into the mechanism of DNA oxidative damage in the development of PINP and implicate PARP-1 as a possible therapeutic target for clinical PINP treatment.

53BP1 loss elicits cGAS-STING-dependent antitumor immunity in ovarian and pancreatic cancer.

53BP1 nucleates the anti-end resection machinery at DNA double-strand breaks, thereby countering BRCA1 activity. Loss of 53BP1 leads to DNA end processing and homologous recombination in BRCA1-deficient cells. Consequently, BRCA1-mutant tumors, typically sensitive to PARP inhibitors (PARPi), become resistant in the absence of 53BP1. Here, we demonstrate that the 'leaky' DNA end resection in the absence of 53BP1 results in increased micronuclei and cytoplasmic double-stranded DNA, leading to activation of the cGAS-STING pathway and pro-inflammatory signaling. This enhances CD8+ T cell infiltration, activates macrophages and natural killer cells, and impedes tumor growth. Loss of 53BP1 correlates with a response to immune checkpoint blockade (ICB) and improved overall survival. Immunohistochemical assessment of 53BP1 in two malignancies, high grade serous ovarian cancer and pancreatic ductal adenocarcinoma, which are refractory to ICBs, reveals that lower 53BP1 levels correlate with an increased adaptive and innate immune response. Finally, BRCA1-deficient tumors that develop resistance to PARPi due to the loss of 53BP1 are susceptible to ICB. Therefore, we conclude that 53BP1 is critical for tumor immunogenicity and underpins the response to ICB. Our results support including 53BP1 expression as an exploratory biomarker in ICB trials for malignancies typically refractory to immunotherapy.

A nanoplatform based on allylthiopurine bio-MOF and glycosylated AIE PARP inhibitor for cancer synthetic lethal therapy.

A biological nanoplatform (Gal-ANI@ZnAP NPs) was constructed based on a prodrug-skeletal metal-organic framework (MOF) using purine nucleobase analogue prodrug 6-allylthiopurine as a bioactive ligand, and functionalized with AIE fluorescent PARP inhibitor glycoconjugate for visualization therapy and synthetic lethal cancer therapy. This nanoplatform could actively target cancer cells, selectively release drugs in response to esterase/pH, and visualize drug uptake. In vitro studies revealed that Gal-ANI@ZnAP NPs increased the synthetic lethality in cancer cells by inducing DNA repair failure with the simultaneous targeting of PARP and nucleotide metabolism, thereby exhibiting a significant cancer-killing effect. The study presents a novel strategy to construct an AIE nanoplatform using pharmaceutical molecules for drug uptake visualization and boosting synthetic lethality in cancer.

CHD1L Regulates Cell Survival in Breast Cancer and Its Inhibition by OTI-611 Impedes the DNA Damage Response and Induces PARthanatos.

The Chromodomain helicase DNA-binding protein 1-like (CHD1L) is a nucleosome remodeling enzyme, which plays a key role in chromatin relaxation during the DNA damage response. Genome editing has shown that deletion of CHD1L sensitizes cells to PARPi, but the effect of its pharmacological inhibition has not been defined. Triple-negative breast cancer SUM149PT, HCC1937, and MDA-MB-231 cells were used to assess the mechanism of action of the CHD1Li OTI-611. Cytotoxicity as a single agent or in combination with standard-of-care treatments was assessed in tumor organoids. Immunofluorescence was used to assess the translocation of PAR and AIF to the cytoplasm or the nucleus and to study markers of DNA damage or apoptosis. Trapping of PARP1/2 or CHD1L onto chromatin was also assessed by in situ subcellular fractionation and immunofluorescence and validated by Western blot. We show that the inhibition of CHD1L's ATPase activity by OTI-611 is cytotoxic to triple-negative breast cancer tumor organoids and synergizes with PARPi and chemotherapy independently of the BRCA mutation status. The inhibition of the remodeling function blocks the phosphorylation of H2AX, traps CHD1L on chromatin, and leaves PAR chains on PARP1/2 open for hydrolysis. PAR hydrolysis traps PARP1/2 at DNA damage sites and mediates PAR translocation to the cytoplasm, release of AIF from the mitochondria, and induction of PARthanatos. The targeted inhibition of CHD1L's oncogenic function by OTI-611 signifies an innovative therapeutic strategy for breast cancer and other cancers. This approach capitalizes on CHD1L-mediated DNA repair and cell survival vulnerabilities, thereby creating synergy with standard-of-care therapies.

PARP enzymes and mono-ADP-ribosylation: advancing the connection from interferon-signalling to cancer biology.

ADP-ribosyltransferases of the PARP family encompass a group of enzymes with variegated regulatory functions in cells, ranging from DNA damage repair to the control of cell-cycle progression and immune response. Over the years, this knowledge has led to the use of PARP1/2 inhibitors as mainstay pharmaceutical strategies for the treatment of ovarian, pancreatic, prostate and breast cancers, holding mutations in genes encoding for proteins involved in the DNA repair mechanisms (synthetic lethality). Meanwhile, the last decade has witnessed significant progress in comprehending cellular pathways regulated by mono-ADP-ribosylation, with a huge effort in the development of novel selective compounds to inhibit those PARPs endowed with mono-ADP-ribosylation activity. This review focuses on the progress achieved in the cancer field, delving into most recent findings regarding the role of a subset of enzymes - the interferon-stimulated PARPs - in cancer progression.

PINX1 loss confers susceptibility to PARP inhibition in pan-cancer cells.

PARP1 is crucial in DNA damage repair, chromatin remodeling, and transcriptional regulation. The principle of synthetic lethality has effectively guided the application of PARP inhibitors in treating tumors carrying BRCA1/2 mutations. Meanwhile, PARP inhibitors have exhibited efficacy in BRCA-proficient patients, further highlighting the necessity for a deeper understanding of PARP1 function and its inhibition in cancer therapy. Here, we unveil PIN2/TRF1-interacting telomerase inhibitor 1 (PINX1) as an uncharacterized PARP1-interacting protein that synergizes with PARP inhibitors upon its depletion across various cancer cell lines. Loss of PINX1 compromises DNA damage repair capacity upon etoposide treatment. The vulnerability of PINX1-deficient cells to etoposide and PARP inhibitors could be effectively restored by introducing either a full-length or a mutant form of PINX1 lacking telomerase inhibitory activity. Mechanistically, PINX1 is recruited to DNA lesions through binding to the ZnF3-BRCT domain of PARP1, facilitating the downstream recruitment of the DNA repair factor XRCC1. In the absence of DNA damage, PINX1 constitutively binds to PARP1, promoting PARP1-chromatin association and transcription of specific DNA damage repair proteins, including XRCC1, and transcriptional regulators, including GLIS3. Collectively, our findings identify PINX1 as a multifaceted partner of PARP1, crucial for safeguarding cells against genotoxic stress and emerging as a potential candidate for targeted tumor therapy.

Application of PARP inhibitors combined with immune checkpoint inhibitors in ovarian cancer.

The advent of polyadenosine diphosphate ribose polymerase inhibitors (PARPi) has brought about significant changes in the field of ovarian cancer treatment. However, in 2022, Rucaparib, Olaparib, and Niraparib, had their marketing approval revoked for third-line and subsequent therapies due to an increased potential for adverse events. Consequently, the exploration of new treatment modalities remains imperative. Recently, the integration of PARPi with immune checkpoint inhibitors (ICIs) has emerged as a potential remedy option within the context of ovarian cancer. This article offers a comprehensive examination of the mechanisms and applications of PARPi and ICIs in the treatment of ovarian cancer. It synthesizes the existing evidence supporting their combined use and discusses key considerations that merit attention in ongoing development efforts.