Poly (ADP-ribose) polymerase inhibitor therapy and mechanisms of resistance in epithelial ovarian cancer.

Advanced epithelial ovarian cancer is the commonest cause of gynaecological cancer deaths. First-line treatment for advanced disease includes a combination of platinum-taxane chemotherapy (post-operatively or peri-operatively) and maximal debulking surgery whenever feasible. Initial response rate to chemotherapy is high (up to 80%) but most patients will develop recurrence (approximately 70-90%) and succumb to the disease. Recently, poly-ADP-ribose polymerase (PARP) inhibition (by drugs such as Olaparib, Niraparib or Rucaparib) directed synthetic lethality approach in BRCA germline mutant or platinum sensitive disease has generated real hope for patients. PARP inhibitor (PARPi) maintenance therapy can prolong survival but therapeutic response is not sustained due to intrinsic or acquired secondary resistance to PARPi therapy. Reversion of BRCA1/2 mutation can lead to clinical PARPi resistance in BRCA-germline mutated ovarian cancer. However, in the more common platinum sensitive sporadic HGSOC, the clinical mechanisms of development of PARPi resistance remains to be defined. Here we provide a comprehensive review of the current status of PARPi and the mechanisms of resistance to therapy.

Inhibition of autophagy as a novel treatment for neurofibromatosis type 1 tumors.

Neurofibromatosis type 1 (NF1) is a genetic disorder caused by mutation of the NF1 gene that is associated with various symptoms, including the formation of benign tumors, called neurofibromas, within nerves. Drug treatments are currently limited. The mitogen-activated protein kinase kinase (MEK) inhibitor selumetinib is used for a subset of plexiform neurofibromas (PNs) but is not always effective and can cause side effects. Therefore, there is a clear need to discover new drugs to target NF1-deficient tumor cells. Using a Drosophila cell model of NF1, we performed synthetic lethal screens to identify novel drug targets. We identified 54 gene candidates, which were validated with variable dose analysis as a secondary screen. Pathways associated with five candidates could be targeted using existing drugs. Among these, chloroquine (CQ) and bafilomycin A1, known to target the autophagy pathway, showed the greatest potential for selectively killing NF1-deficient Drosophila cells. When further investigating autophagy-related genes, we found that 14 out of 30 genes tested had a synthetic lethal interaction with NF1. These 14 genes are involved in multiple aspects of the autophagy pathway and can be targeted with additional drugs that mediate the autophagy pathway, although CQ was the most effective. The lethal effect of autophagy inhibitors was conserved in a panel of human NF1-deficient Schwann cell lines, highlighting their translational potential. The effect of CQ was also conserved in a Drosophila NF1 in vivo model and in a xenografted NF1-deficient tumor cell line grown in mice, with CQ treatment resulting in a more significant reduction in tumor growth than selumetinib treatment. Furthermore, combined treatment with CQ and selumetinib resulted in a further reduction in NF1-deficient cell viability. In conclusion, NF1-deficient cells are vulnerable to disruption of the autophagy pathway. This pathway represents a promising target for the treatment of NF1-associated tumors, and we identified CQ as a candidate drug for the treatment of NF1 tumors.

Simultaneous inhibition of ATM, ATR, and DNA-PK causes synergistic lethality.

Here we report that simultaneous inhibition of the three primary DNA damage recognition PI3 kinase-like kinases (PIKKs) -ATM, ATR, and DNA-PK- induces severe combinatorial synthetic lethality in mammalian cells. Utilizing Chinese hamster cell lines CHO and V79 and their respective PIKK mutants, we evaluated effects of inhibiting these three kinases on cell viability, DNA damage response, and chromosomal integrity. Our results demonstrate that while single or dual kinase inhibition increased cytotoxicity, inhibition of all three PIKKs results in significantly higher synergistic lethality, chromosomal aberrations, and DNA double-strand break (DSB) induction as calculated by their synergy scores. These findings suggest that the overlapping redundancy of ATM, ATR, and DNA-PK functions is critical for cell survival, and their combined inhibition greatly disrupts DNA damage signaling and repair processes, leading to cell death. This study provides insights into the potential of multi-targeted DDR kinase inhibition as an effective anticancer strategy, necessitating further research to elucidate underlying mechanisms and therapeutic applications.

Factors influencing the research impact in cancer research: a collaboration and knowledge network analysis.

BACKGROUND: Cancer is a major public health challenge globally. However, little is known about the evolution patterns of cancer research communities and the influencing factors of their research capacity and impact, which is affected not only by the social networks established through research collaboration but also by the knowledge networks in which the research projects are embedded. METHODS: The focus of this study was narrowed to a specific topic - 'synthetic lethality' - in cancer research. This field has seen vibrant growth and multidisciplinary collaboration in the past decade. Multi-level collaboration and knowledge networks were established and analysed on the basis of bibliometric data from 'synthetic lethality'-related cancer research papers. Negative binomial regression analysis was further applied to explore how node attributes within these networks, along with other potential factors, affected paper citations, which are widely accepted as proxies for assessing research capacity and impact. RESULTS: Our study revealed that the synthetic lethality-based cancer research field is characterized by a knowledge network with high integration, alongside a collaboration network exhibiting some clustering. We found significant correlations between certain factors and citation counts. Specifically, a leading status within the nation-level international collaboration network and industry involvement were both found to be significantly related to higher citations. In the individual-level collaboration networks, lead authors' degree centrality has an inverted U-shaped relationship with citations, while their structural holes exhibit a positive and significant effect. Within the knowledge network, however, only measures of structural holes have a positive and significant effect on the number of citations. CONCLUSIONS: To enhance cancer research capacity and impact, non-leading countries should take measures to enhance their international collaboration status. For early career researchers, increasing the number of collaborators seems to be more effective. University-industry cooperation should also be encouraged, enhancing the integration of human resources, technology, funding, research platforms and medical resources. Insights gained through this study also provide recommendations to researchers or administrators in designing future research directions from a knowledge network perspective. Focusing on unique issues especially interdisciplinary fields will improve output and influence their research work.

Tumor Treating Fields (TTFields) induce homologous recombination deficiency in ovarian cancer cells, thus mitigating drug resistance.

Background: Ovarian cancer is the leading cause of mortality among gynecological malignancies. Carboplatin and poly (ADP-ribose) polymerase inhibitors (PARPi) are often implemented in the treatment of ovarian cancer. Homologous recombination deficient (HRD) tumors demonstrate increased sensitivity to these treatments; however, many ovarian cancer patients are homologous recombination proficient (HRP). TTFields are non-invasive electric fields that induce an HRD-like phenotype in various cancer types. The current study aimed to investigate the impact of TTFields applied together with carboplatin or PARPi (olaparib or niraparib) in preclinical ovarian cancer models. Methods: A2780 (HRP), OVCAR3 (HRD), and A2780cis (platinum-resistant) human ovarian cancer cells were treated in vitro with TTFields (1 V/cm RMS, 200 kHz, 72 h), alone or with various drug concentrations. Treated cells were measured for cell count, colony formation, apoptosis, DNA damage, expression of DNA repair proteins, and cell cycle. In vivo, ID8-fLuc (HRP) ovarian cancer cells were inoculated intraperitoneally to C57BL/6 mice, which were then treated with either sham, TTFields (200 kHz), olaparib (50 mg/kg), or TTFields plus olaparib; over a period of four weeks. Tumor growth was analyzed using bioluminescent imaging at treatment cessation; and survival analysis was performed. Results: The nature of TTFields-drug interaction was dependent on the drug's underlying mechanism of action and on the genetic background of the cells, with synergistic interactions between TTFields and carboplatin or PARPi seen in HRP and resistant cells. Treated cells demonstrated elevated levels of DNA damage, accompanied by G2/M arrest, and induction of an HRD-like phenotype. In the tumor-bearing mice, TTFields and olaparib co-treatment resulted in reduced tumor volume and a survival benefit relative to olaparib monotherapy and to control. Conclusion: By inducing an HRD-like phenotype, TTFields sensitize HRP and resistant ovarian cancer cells to treatment with carboplatin or PARPi, potentially mitigating a-priori and de novo drug resistance, a major limitation in ovarian cancer treatment.

Identifying actionable synthetically lethal cancer gene pairs using mutual exclusivity.

Mutually exclusive loss-of-function alterations in gene pairs are those that occur together less frequently than may be expected and may denote a synthetically lethal relationship (SSL) between the genes. SSLs can be exploited therapeutically to selectively kill cancer cells. Here, we analysed mutation, copy number variation, and methylation levels in samples from The Cancer Genome Atlas, using the hypergeometric and the Poisson binomial tests to identify mutually exclusive inactivated genes. We focused on gene pairs where one is an inactivated tumour suppressor and the other a gene whose protein product can be inhibited by known drugs. This provided an abundance of potential targeted therapeutics and repositioning opportunities for several cancers. These data are available on the MexDrugs website, https://bioinformaticslab.sussex.ac.uk/mexdrugs.

Methylation of FAM110C is a synthetic lethal marker for ATR/CHK1 inhibitors in pancreatic cancer.

Background and objectives: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies. An epigenetic-based synthetic lethal strategy provides a novel opportunity for PDAC treatment. Finding more DNA damage repair (DDR)-related or cell fate-related molecules with aberrant epigenetic changes is becoming very important. Family with sequence similarity 110C (FAM110C) is a cell fate-related gene and its function in cancer remains unclear. Methods: Seven cell lines, 34 cases of intraductal papillary mucinous neoplasm (IPMN), 15 cases of mucinous cystic neoplasm (MCN) and 284 cases of PDAC samples were employed. Methylation-specific PCR, western blot, CRISPR knockout, immunoprecipitation and a xenograft mouse model were used in this study. Results: FAM110C is methylated in 41.18% (14/34) of IPMN, 46.67% (7/15) of MCN and 72.89% (207/284) of PDAC, with a progression trend from IPMN/MCN to pancreatic cancer (P = 0.0001, P = 0.0389). FAM110C methylation is significantly associated with poor overall survival (OS) (P = 0.0065) and is an independent prognostic marker for poor OS (P = 0.0159). FAM110C inhibits PDAC cells growth both in vitro and in vivo, serving as a novel tumor suppressor. FAM110C activates ATM and NHEJ signaling pathways by interacting with HMGB1. Loss of FAM110C expression sensitizes PDAC cells to VE-822 (an ATR inhibitor) and MK-8776 (a CHK1 inhibitor). Conclusion: FAM110C methylation is a potential diagnostic and prognostic marker in PDAC, and its epigenetic silencing sensitizes PDAC cells to ATR/CHK1 inhibitors.

Systematic analysis of microorganisms' metabolism for selective targeting.

Selective drugs with a relatively narrow spectrum can reduce the side effects of treatments compared to broad-spectrum antibiotics by specifically targeting the pathogens responsible for infection. Furthermore, combating an infectious pathogen, especially a drug-resistant microorganism, is more efficient by attacking multiple targets. Here, we combined synthetic lethality with selective drug targeting to identify multi-target and organism-specific potential drug candidates by systematically analyzing the genome-scale metabolic models of six different microorganisms. By considering microorganisms as targeted or conserved in groups ranging from one to six members, we designed 665 individual case studies. For each case, we identified single essential reactions as well as double, triple, and quadruple synthetic lethal reaction sets that are lethal for targeted microorganisms and neutral for conserved ones. As expected, the number of obtained solutions for each case depends on the genomic similarity between the studied microorganisms. Mapping the identified potential drug targets to their corresponding pathways highlighted the importance of key subsystems such as cell envelope biosynthesis, glycerophospholipid metabolism, membrane lipid metabolism, and the nucleotide salvage pathway. To assist in the validation and further investigation of our proposed potential drug targets, we introduced two sets of targets that can theoretically address a substantial portion of the 665 cases. We expect that the obtained solutions provide valuable insights into designing narrow-spectrum drugs that selectively cause system-wide damage only to the target microorganisms.

Synthetic lethal CRISPR screen identifies a cancer cell-intrinsic role of PD-L1 in regulation of vulnerability to ferroptosis.

Despite the success of programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibition in tumor therapy, many patients do not benefit. This failure may be attributed to the intrinsic functions of PD-L1. We perform a genome-wide CRISPR synthetic lethality screen to systematically explore the intrinsic functions of PD-L1 in head and neck squamous cell carcinoma (HNSCC) cells, identifying ferroptosis-related genes as essential for the viability of PD-L1-deficient cells. Genetic and pharmacological induction of ferroptosis accelerates cell death in PD-L1 knockout cells, which are also more susceptible to immunogenic ferroptosis. Mechanistically, nuclear PD-L1 transcriptionally activates SOD2 to maintain redox homeostasis. Lower reactive oxygen species (ROS) and ferroptosis are observed in patients with HNSCC who have higher PD-L1 expression. Our study illustrates that PD-L1 confers ferroptosis resistance in HNSCC cells by activating the SOD2-mediated antioxidant pathway, suggesting that targeting the intrinsic functions of PD-L1 could enhance therapeutic efficacy.

Regulation, functional impact, and therapeutic targeting of APOBEC3A in cancer.

Enzymes of the apolipoprotein B mRNA editing catalytic polypeptide like (APOBEC) family are cytosine deaminases that convert cytosine to uracil in DNA and RNA. Among these proteins, APOBEC3 sub-family members, APOBEC3A (A3A) and APOBEC3B (A3B), are prominent sources of mutagenesis in cancer cells. The aberrant expression of A3A and A3B in cancer cells leads to accumulation of mutations with specific single-base substitution (SBS) signatures, characterized by C→T and C→G changes, in a number of tumor types. In addition to fueling mutagenesis, A3A and A3B, particularly A3A, induce DNA replication stress, DNA damage, and chromosomal instability through their catalytic activities, triggering a range of cellular responses. Thus, A3A/B have emerged as key drivers of genome evolution during cancer development, contributing to tumorigenesis, tumor heterogeneity, and therapeutic resistance. Yet, the expression of A3A/B in cancer cells presents a cancer vulnerability that can be exploited therapeutically. In this review, we discuss the recent studies that shed light on the mechanisms regulating A3A expression and the impact of A3A in cancer. We also review recent advances in the development of A3A inhibitors and provide perspectives on the future directions of A3A research.

MPASL: multi-perspective learning knowledge graph attention network for synthetic lethality prediction in human cancer.

Synthetic lethality (SL) is widely used to discover the anti-cancer drug targets. However, the identification of SL interactions through wet experiments is costly and inefficient. Hence, the development of efficient and high-accuracy computational methods for SL interactions prediction is of great significance. In this study, we propose MPASL, a multi-perspective learning knowledge graph attention network to enhance synthetic lethality prediction. MPASL utilizes knowledge graph hierarchy propagation to explore multi-source neighbor nodes related to genes. The knowledge graph ripple propagation expands gene representations through existing gene SL preference sets. MPASL can learn the gene representations from both gene-entity perspective and entity-entity perspective. Specifically, based on the aggregation method, we learn to obtain gene-oriented entity embeddings. Then, the gene representations are refined by comparing the various layer-wise neighborhood features of entities using the discrepancy contrastive technique. Finally, the learned gene representation is applied in SL prediction. Experimental results demonstrated that MPASL outperforms several state-of-the-art methods. Additionally, case studies have validated the effectiveness of MPASL in identifying SL interactions between genes.

Mitoferrin2 is a synthetic lethal target for chromosome 8p deleted cancers.

BACKGROUND: Somatic copy number alterations are a hallmark of cancer that offer unique opportunities for therapeutic exploitation. Here, we focused on the identification of specific vulnerabilities for tumors harboring chromosome 8p deletions. METHODS: We developed and applied an integrative analysis of The Cancer Genome Atlas (TCGA), the Cancer Dependency Map (DepMap), and the Cancer Cell Line Encyclopedia to identify chromosome 8p-specific vulnerabilities. We employ orthogonal gene targeting strategies, both in vitro and in vivo, including short hairpin RNA-mediated gene knockdown and CRISPR/Cas9-mediated gene knockout to validate vulnerabilities. RESULTS: We identified SLC25A28 (also known as MFRN2), as a specific vulnerability for tumors harboring chromosome 8p deletions. We demonstrate that vulnerability towards MFRN2 loss is dictated by the expression of its paralog, SLC25A37 (also known as MFRN1), which resides on chromosome 8p. In line with their function as mitochondrial iron transporters, MFRN1/2 paralog protein deficiency profoundly impaired mitochondrial respiration, induced global depletion of iron-sulfur cluster proteins, and resulted in DNA-damage and cell death. MFRN2 depletion in MFRN1-deficient tumors led to impaired growth and even tumor eradication in preclinical mouse xenograft experiments, highlighting its therapeutic potential. CONCLUSIONS: Our data reveal MFRN2 as a therapeutic target of chromosome 8p deleted cancers and nominate MFNR1 as the complimentary biomarker for MFRN2-directed therapies.

IMPDH Inhibition Decreases TERT Expression and Synergizes the Cytotoxic Effect of Chemotherapeutic Agents in Glioblastoma Cells.

IMP dehydrogenase (IMPDH) inhibition has emerged as a new target therapy for glioblastoma multiforme (GBM), which remains one of the most refractory tumors to date. TCGA analyses revealed distinct expression profiles of IMPDH isoenzymes in various subtypes of GBM and low-grade glioma (LGG). To dissect the mechanism(s) underlying the anti-tumor effect of IMPDH inhibition in adult GBM, we investigated how mycophenolic acid (MPA, an IMPDH inhibitor) treatment affected key oncogenic drivers in glioblastoma cells. Our results showed that MPA decreased the expression of telomerase reverse transcriptase (TERT) in both U87 and U251 cells, and the expression of O6-methylguanine-DNA methyltransferase (MGMT) in U251 cells. In support, MPA treatment reduced the amount of telomere repeats in U87 and U251 cells. TERT downregulation by MPA was associated with a significant decrease in c-Myc (a TERT transcription activator) in U87 but not U251 cells, and a dose-dependent increase in p53 and CCCTC-binding factor (CTCF) (TERT repressors) in both U87 and U251 cells. In U251 cells, MPA displayed strong cytotoxic synergy with BCNU and moderate synergy with irinotecan, oxaliplatin, paclitaxel, or temozolomide (TMZ). In U87 cells, MPA displayed strong cytotoxic synergy with all except TMZ, acting primarily through the apoptotic pathway. Our work expands the mechanistic potential of IMPDH inhibition to TERT/telomere regulation and reveals a synthetic lethality between MPA and anti-GBM drugs.

NAMPT-targeting PROTAC and nicotinic acid co-administration elicit safe and robust anti-tumor efficacy in NAPRT-deficient pan-cancers.

Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the biosynthesis of nicotinamide adenine dinucleotide (NAD+), making it a potential target for cancer therapy. Two challenges hinder its translation in the clinic: targeting the extracellular form of NAMPT (eNAMPT) remains insufficient, and side effects are observed in normal tissues. We previously utilized proteolysis-targeting chimera (PROTAC) to develop two compounds capable of simultaneously degrading iNAMPT and eNAMPT. Unfortunately, the pharmacokinetic properties were inadequate, and toxicities similar to those associated with traditional inhibitors arose. We have developed a next-generation PROTAC molecule 632005 to address these challenges, demonstrating exceptional target selectivity and bioavailability, improved in vivo exposure, extended half-life, and reduced clearance rate. When combined with nicotinic acid, 632005 exhibits safety and robust efficacy in treating NAPRT-deficient pan-cancers, including xenograft models with hematologic malignancy and prostate cancer and patient-derived xenograft (PDX) models with liver cancer. Our findings provide clinical references for patient selection and treatment strategies involving NAMPT-targeting PROTACs.

Methylation synthetic lethality: Exploiting selective drug targets for cancer therapy.

In cancer, synthetic lethality refers to the drug-induced inactivation of one gene and the inhibition of another in cancer cells by a drug, resulting in the death of only cancer cells; however, this effect is not present in normal cells, leading to targeted killing of cancer cells. Recent intensive epigenetic research has revealed that aberrant epigenetic changes are more frequently observed than gene mutations in certain cancers. Recently, numerous studies have reported various methylation synthetic lethal combinations involving DNA damage repair genes, metabolic pathway genes, and paralogs with significant results in cellular models, some of which have already entered clinical trials with promising results. This review systematically introduces the advantages of methylation synthetic lethality and describes the lethal mechanisms of methylation synthetic lethal combinations that have recently demonstrated success in cellular models. Furthermore, we discuss the future opportunities and challenges of methylation synthetic lethality in targeted anticancer therapies.

Synthetic lethality and the minimal genome size problem.

Gene knockout studies suggest that ~300 genes in a bacterial genome and ~1,100 genes in a yeast genome cannot be deleted without loss of viability. These single-gene knockout experiments do not account for negative genetic interactions, when two or more genes can each be deleted without effect, but their joint deletion is lethal. Thus, large-scale single-gene deletion studies underestimate the size of a minimal gene set compatible with cell survival. In yeast Saccharomyces cerevisiae, the viability of all possible deletions of gene pairs (2-tuples), and of some deletions of gene triplets (3-tuples), has been experimentally tested. To estimate the size of a yeast minimal genome from that data, we first established that finding the size of a minimal gene set is equivalent to finding the minimum vertex cover in the lethality (hyper)graph, where the vertices are genes and (hyper)edges connect k-tuples of genes whose joint deletion is lethal. Using the Lovász-Johnson-Chvatal greedy approximation algorithm, we computed the minimum vertex cover of the synthetic-lethal 2-tuples graph to be 1,723 genes. We next simulated the genetic interactions in 3-tuples, extrapolating from the existing triplet sample, and again estimated minimum vertex covers. The size of a minimal gene set in yeast rapidly approaches the size of the entire genome even when considering only synthetic lethalities in k-tuples with small k. In contrast, several studies reported successful experimental reductions of yeast and bacterial genomes by simultaneous deletions of hundreds of genes, without eliciting synthetic lethality. We discuss possible reasons for this apparent contradiction.IMPORTANCEHow can we estimate the smallest number of genes sufficient for a unicellular organism to survive on a rich medium? One approach is to remove genes one at a time and count how many of such deletion strains are unable to grow. However, the single-gene knockout data are insufficient, because joint gene deletions may result in negative genetic interactions, also known as synthetic lethality. We used a technique from graph theory to estimate the size of minimal yeast genome from partial data on synthetic lethality. The number of potential synthetic lethal interactions grows very fast when multiple genes are deleted, revealing a paradoxical contrast with the experimental reductions of yeast genome by ~100 genes, and of bacterial genomes by several hundreds of genes.

Pan-cancer proteogenomics expands the landscape of therapeutic targets.

Fewer than 200 proteins are targeted by cancer drugs approved by the Food and Drug Administration (FDA). We integrate Clinical Proteomic Tumor Analysis Consortium (CPTAC) proteogenomics data from 1,043 patients across 10 cancer types with additional public datasets to identify potential therapeutic targets. Pan-cancer analysis of 2,863 druggable proteins reveals a wide abundance range and identifies biological factors that affect mRNA-protein correlation. Integration of proteomic data from tumors and genetic screen data from cell lines identifies protein overexpression- or hyperactivation-driven druggable dependencies, enabling accurate predictions of effective drug targets. Proteogenomic identification of synthetic lethality provides a strategy to target tumor suppressor gene loss. Combining proteogenomic analysis and MHC binding prediction prioritizes mutant KRAS peptides as promising public neoantigens. Computational identification of shared tumor-associated antigens followed by experimental confirmation nominates peptides as immunotherapy targets. These analyses, summarized at https://targets.linkedomics.org, form a comprehensive landscape of protein and peptide targets for companion diagnostics, drug repurposing, and therapy development.

[18F]F-Poly(ADP-Ribose) Polymerase Inhibitor Radiotracers for Imaging PARP Expression and Their Potential Clinical Applications in Oncology.

Including poly(ADP-ribose) polymerase (PARP) inhibitors in managing patients with inoperable tumors has significantly improved outcomes. The PARP inhibitors hamper single-strand deoxyribonucleic acid (DNA) repair by trapping poly(ADP-ribose)polymerase (PARP) at sites of DNA damage, forming a non-functional "PARP enzyme-inhibitor complex" leading to cell cytotoxicity. The effect is more pronounced in the presence of PARP upregulation and homologous recombination (HR) deficiencies such as breast cancer-associated gene (BRCA1/2). Hence, identifying HR-deficiencies by genomic analysis-for instance, BRCA1/2 used in triple-negative breast cancer-should be a part of the selection process for PARP inhibitor therapy. Published data suggest BRCA1/2 germline mutations do not consistently predict favorable responses to PARP inhibitors, suggesting that other factors beyond tumor mutation status may be at play. A variety of factors, including tumor heterogeneity in PARP expression and intrinsic and/or acquired resistance to PARP inhibitors, may be contributing factors. This justifies the use of an additional tool for appropriate patient selection, which is noninvasive, and capable of assessing whole-body in vivo PARP expression and evaluating PARP inhibitor pharmacokinetics as complementary to the currently available BRCA1/2 analysis. In this review, we discuss [18F]Fluorine PARP inhibitor radiotracers and their potential in the imaging of PARP expression and PARP inhibitor pharmacokinetics. To provide context we also briefly discuss possible causes of PARP inhibitor resistance or ineffectiveness. The discussion focuses on TNBC, which is a tumor type where PARP inhibitors are used as part of the standard-of-care treatment strategy.

Epigenetic silencing of BEND4, a novel DNA damage repair gene, is a synthetic lethal marker for ATM inhibitor in pancreatic cancer.

Synthetic lethality is a novel model for cancer therapy. To understand the function and mechanism of BEN domain-containing protein 4 (BEND4) in pancreatic cancer, eight cell lines and a total of 492 cases of pancreatic neoplasia samples were included in this study. Methylation-specific polymerase chain reaction, CRISPR/Cas9, immunoprecipitation assay, comet assay, and xenograft mouse model were used. BEND4 is a new member of the BEN domain family. The expression of BEND4 is regulated by promoter region methylation. It is methylated in 58.1% (176/303) of pancreatic ductal adenocarcinoma (PDAC), 33.3% (14/42) of intraductal papillary mucinous neoplasm, 31.0% (13/42) of pancreatic neuroendocrine tumor, 14.3% (3/21) of mucinous cystic neoplasm, 4.3% (2/47) of solid pseudopapillary neoplasm, and 2.7% (1/37) of serous cystic neoplasm. BEND4 methylation is significantly associated with late-onset PDAC (> 50 years, P < 0.01) and tumor differentiation (P < 0.0001), and methylation of BEND4 is an independent poor prognostic marker (P < 0.01) in PDAC. Furthermore, BEND4 plays tumor-suppressive roles in vitro and in vivo. Mechanistically, BEND4 involves non-homologous end joining signaling by interacting with Ku80 and promotes DNA damage repair. Loss of BEND4 increased the sensitivity of PDAC cells to ATM inhibitor. Collectively, the present study revealed an uncharacterized tumor suppressor BEND4 and indicated that methylation of BEND4 may serve as a potential synthetic lethal marker for ATM inhibitor in PDAC treatment.

Chromothripsis: an emerging crossroad from aberrant mitosis to therapeutic opportunities.

Chromothripsis, a type of complex chromosomal rearrangement originally known as chromoanagenesis, has been a subject of extensive investigation due to its potential role in various diseases, particularly cancer. Chromothripsis involves the rapid acquisition of tens to hundreds of structural rearrangements within a short period, leading to complex alterations in one or a few chromosomes. This phenomenon is triggered by chromosome missegregation during mitosis. Errors in accurate chromosome segregation lead to formation of aberrant structural entities such as micronuclei or chromatin bridges. The association between chromothripsis and cancer has attracted significant interest, with potential implications for tumorigenesis and disease prognosis. This review aims to explore the intricate mechanisms and consequences of chromothripsis, with a specific focus on its association with mitotic perturbations. Herein, we discuss a comprehensive analysis of crucial molecular entities and pathways, exploring the intricate roles of the CIP2A-TOPBP1 complex, micronuclei formation, chromatin bridge processing, DNA damage repair, and mitotic checkpoints. Moreover, the review will highlight recent advancements in identifying potential therapeutic targets and the underlying molecular mechanisms associated with chromothripsis, paving the way for future therapeutic interventions in various diseases.