DNA repair and synthetic lethality

Tumors often have DNA repair defects, suggesting additional inhibition of other DNA repair pathways in tumors may lead to synthetic lethality. Accumulating data demonstrate that DNA repair-defective tumors, in particular homologous recombination （HR）, are highly sensitive to DNA-damaging agents. Thus, HR-defective tumors exhibit potential vulnerability to the synthetic lethality approach, which may lead to new therapeutic strategies. It is well known that poly （adenosine diphosphate （ADP）-ribose） polymerase （PARP） inhibitors show the synthetically lethal effect in tumors defective in BRCA1 or BRCA2 genes encoded proteins that are required for efficient HR. In this review, we summarize the strategies of targeting DNA repair pathways and other DNA metabolic functions to cause synthetic lethality in HR-defective tumor cells.

Cyclin-dependent kinases-based synthetic lethality: Evidence, concept, and strategy

Synthetic lethality is a proven effective antitumor strategy that has attracted great attention.Large-scale screening has revealed many synthetic lethal genetic phenotypes,and relevant smallmolecule drugs have also been implemented in clinical practice.Increasing evidence suggests that CDKs,constituting a kinase family predominantly involved in cell cycle control,are synthetic lethal factors when combined with certain oncogenes,such as MFC,TP53,and RAS,which facilitate numerous antitumor treatment options based on CDK-related synthetic lethality.In this review,we focus on the synthetic lethal phenotype and mechanism related to CDKs and summarize the preclinical and clinical discoveries of CDK inhibitors to explore the prospect of CDK inhibitors as antitumor compounds for strategic synthesis lethality in the future.

Targeting“undruggable”c-Myc protein by synthetic lethality

Synthetic lethal screening,which exploits the combination of mutations that result in cell death,is a promising method for identifying novel drug targets.This method provides a new avenue for targeting Uundruggable,9 proteins,such as c-Myc.Here,we revisit current methods used to target c-Myc and discuss the important functional nodes related to c-Myc in non-oncogene addicted network,whose inhibition may cause a catastrophe for tumor cell destiny but not for normal cells.We further discuss strategies to identify these functional nodes in the context of synthetic lethality.We review the progress and shortcomings of this research field and look forward to opportunities offered by synthetic lethal screening to treat tumors potently.

Epigenetic silencing schlafen-11 sensitizes esophageal cancer to ATM inhibitor

BACKGROUND Targeting DNA damage response(DDR)pathway is a cutting-edge strategy.It has been reported that Schlafen-11(SLFN11)contributes to increase chemosensitivity by participating in DDR.However,the detailed mechanism is unclear.AIM To investigate the role of SLFN11 in DDR and the application of synthetic lethal in esophageal cancer with SLFN11 defects.METHODS To reach the purpose,eight esophageal squamous carcinoma cell lines,142 esophageal dysplasia(ED)and 1007 primary esophageal squamous cell carcinoma(ESCC)samples and various techniques were utilized,including methylationspecific polymerase chain reaction,CRISPR/Cas9 technique,Western blot,colony formation assay,and xenograft mouse model.RESULTS Methylation of SLFN11 was exhibited in 9.15%of(13/142)ED and 25.62%of primary(258/1007)ESCC cases,and its expression was regulated by promoter region methylation.SLFN11 methylation was significantly associated with tumor differentiation and tumor size(both P<0.05).However,no significant associations were observed between promoter region methylation and age,gender,smoking,alcohol consumption,TNM stage,or lymph node metastasis.Utilizing DNA damaged model induced by low dose cisplatin,SLFN11 was found to activate non-homologous end-joining and ATR/CHK1 signaling pathways,while inhibiting the ATM/CHK2 signaling pathway.Epigenetic silencing of SLFN11 was found to sensitize the ESCC cells to ATM inhibitor(AZD0156),both in vitro and in vivo.CONCLUSION SLFN11 is frequently methylated in human ESCC.Methylation of SLFN11 is sensitive marker of ATM inhibitor in ESCC.

A combination therapy for KRAS-mutant lung cancer by targeting synthetic lethal partners of mutant KRAS

The KRAS gene is frequently mutated in multiple cancer types,but it fell off the drug discovery radar for many years because of its inherent "undruggable" structure and undefined biological properties.As reported in the paper entitled "Suppression of KRas-mutant cancer through the combined inhibition of KRAS with PLK1 and ROCK" in Nature Communications,we performed a synthetic lethal screening with a combinatorial strategy on a panel of clinical drugs;we found that combined inhibition of polo-like kinase 1 and RhoA/Rho kinase markedly suppressed tumor growth in mice.An increase in the expression of the tumor suppressor P21^(WAF1/CIP1) contributed to the synergistic mechanism of the combination therapy.These findings open a novel avenue for the treatment of KRAS-mutant lung cancer.

Mechanism of tumor synthetic lethal-related targets

Synthetic lethality is becoming more and more important in the precise treatment of oncology.Malignant tumors caused by gene mutations involve a complex DNA signaling process,and inhibition of DNA signaling in different ways may more effectively control the occurrence and development of tumors.Inhibition of tumor paired lethal genes effectively kills tumor cells,and more and more novel drugs that inhibit tumors are developing in this direction.This article reviews the synthetic lethal theory and discusses selection of drugs to target mutated genes in common solid tumors.The synthetic lethal gene pairs,representative targeted drugs,and related characteristics of four tumor types:lung cancer,breast cancer,colon cancer and prostate cancer,are systematically reviewed.

Targeting DNA repair for cancer treatment: Lessons from PARP inhibitor trials

Ionizing radiation is frequently used to treat solid tumors,as it causes DNA damage and kill cancer cells.However,damaged DNA is repaired involving poly-(ADP-ribose)polymerase-1(PARP-1)causing resistance to radiation therapy.Thus,PARP-1 represents an important target in multiple cancer types,including prostate cancer.PARP is a nuclear enzyme essential for single-strand DNA breaks repair.Inhibiting PARP-1 is lethal in a wide range of cancer cells that lack the homologous recombination repair(HR)pathway.This article provides a concise and simplified overview of the development of PARP inhibitors in the laboratory and their clinical applications.We focused on the use of PARP inhibitors in various cancers,including prostate cancer.We also discussed some of the underlying principles and challenges that may affect the clinical efficacy of PARP inhibitors.

Synthetic lethal approaches to target cancers with loss of PTEN function

Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene and has a role in inhibiting the oncogenic AKT signaling pathway by dephosphorylating phosphatidylinositol 3,4,5-triphosphate (PIP3 ) into phosphatidylinositol 4,5-bisphosphate (PIP2 ). The function of PTEN is regulated by different mechanisms and inactive PTEN results in aggressive tumor phenotype and tumorigenesis. Identifying targeted therapies for inactive tumor suppressor genes such as PTEN has been challenging as it is difficult to restore the tumor suppressor functions. Therefore, focusing on the downstream signaling pathways to discover a targeted therapy for inactive tumor suppressor genes has highlighted the importance of synthetic lethality studies. This review focused on the potential synthetic lethality genes discovered in PTEN-inactive cancer types. These discovered genes could be potential targeted therapies for PTEN-inactive cancer types and may improve the treatment response rates for aggressive types of cancer.

Mechanism of RBBP8-mediated homologous recombination repair in gastric cancer synthetic lethal

Background:It is of great clinical significance to further explore new strategies and potential combined therapeutic targets for gastric cancer.This study aimed to investigate the synthetic lethal effect of RBBP8 molecular intervention combined with a poly ADP ribose polymerase(PARP)inhibitor in non-BRCA mutant gastric cancer and clarify the mechanism by which RBBP8 regulates homologous recombination repair.Methods:The role of RBBP8 in DNA damage repair was observed using bioinformatic analysis,western blot analysis,and immunofluorescence.The synthetic lethal effect was verified using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium,inner salt(MTS)and flow cytometry apoptosis experiments.Results:Among the patients with gastric cancer treated with chemotherapy,the prognosis of patients with high RBBP8 expression levels was worse(homologous recombination[HR]=1.54,p=0.028).RBBP8 knockdown induced DNA damage and had a synergistic effect with PARP inhibitor treatment on cell viability inhibition and cell apoptosis in AGS(generic code for human gastric adenocarcinoma cells)(t=11.154,p<0.001)and N87(t=6.362,p<0.001)cells.RBBP8 knockdown inhibited RAD51 activation and DNA terminal excision in homologous recombination repair.Conclusion:RBBP8 is involved in homologous recombination repair,and molecular intervention into RBBP8 could achieve a synthetic lethal effect with PARP inhibitor treatment in gastric cancer cells.

Combination therapy with androgen deprivation for hormone sensitive prostate cancer: A new frontier

Androgen deprivation therapy(ADT)has been the standard of care for the last 75 years in metastatic hormone sensitive prostate cancer(PCa).However,this approach is rarely curative.Recent clinical trials have demonstrated that ADT combined with other agents,notably docetaxel and abiraterone,lead to improved survival.The mechanisms surrounding this improved cancer outcomes are incompletely defined.The response of cancer cells to ADT includes apoptosis and cell death,but a significant fraction remains viable.Our laboratory has demonstrated both in vitro and in vivo that cellular senescence occurs in a subset of these cells.Cellular senescence is a phenotype characterized by cell cycle arrest,senescenceassociated b-galactosidase(SA-b-gal),and a hypermetabolic state.Positive features of cellular senescence include growth arrest and immune stimulation,although persistence may release cytokines and growth factors that are detrimental.Senescent tumor cells generate a catabolic state with increased glycolysis,protein turnover and other metabolic changes that represent targets for drugs,like metformin,to be applied in a synthetic lethal approach.This review examines the response to ADT and the putative role of cellular senescence as a biomarker and therapeutic target in this context.

From basic researches to new achievements in therapeutic strategies of KRAS-driven cancers

Among the numerous oncogenes involved in human cancers, KRAS represents the most studied and best characterized cancerrelated genes.Several therapeutic strategies targeting oncogenic KRAS(KRASonc) signaling pathways have been suggested,including the inhibition of synthetic lethal interactions, direct inhibition of KRASonc itself, blockade of downstream KRASonc effectors, prevention of post-translational KRASonc modifications, inhibition of the induced stem cell-like program, targeting of metabolic peculiarities, stimulation of the immune system, inhibition of inflammation, blockade of upstream signaling pathways,targeted RNA replacement, and oncogene-induced senescence.Despite intensive and continuous efforts, KRASonc remains an elusive target for cancer therapy.To highlight the progress to date, this review covers a collection of studies on therapeutic strategies for KRAS published from 1995 to date.An overview of the path of progress from earlier to more recent insights highlight novel opportunities for clinical development towards KRASonc-signaling targeted therapeutics.

MOF负载Weel抑制剂实现p53突变胆囊癌的合成致死靶向治疗

Adavosertib(ADA)is a WEE1 inhibitor that exhibits a synthetic lethal effect on p53-mutated gallbladder cancer(GBC).However,drug resistance due to DNA damage response compensation pathways and high toxicity limits further applications.Herein,estrone-targeted ADA-encapsulated metal–organic frameworks(ADA@MOF-EPL)for GBC synthetic lethal treatment by inducing conditional factors are developed.The high expression of estrogen receptors in GBC enables ADA@MOF-EPL to quickly enter and accumulate near the cell nucleus through estrone-mediated endocytosis and release ADA to inhibit WEE1 upon entering the acidic tumor microenvironment.Ultrasound irradiation induces ADA@MOF-EPL to generate reactive oxygen species(ROS),which leads to a further increase in DNA damage,resulting in a higher sensitivity of p53-mutated cancer cells to WEE1 inhibitor and promoting cell death via conditional synthetic lethality.The conditional factor induced by ADA@MOF-EPL further enhances the antitumor efficacy while significantly reducing systemic toxicity.Moreover,ADA@MOF-EPL demonstrates similar antitumor abilities in other p53-mutated solid tumors,revealing its potential as a broad-spectrum antitumor drug.

Synthetic Lethal Interactions Prediction Based on Multiple Similarity Measures Fusion

The synthetic lethality(SL)relationship arises when a combination of deficiencies in two genes leads to cell death,whereas a deficiency in either one of the two genes does not.The survival of the mutant tumor cells depends on the SL partners of the mutant gene,thereby the cancer cells could be selectively killed by inhibiting the SL partners of the oncogenic genes but normal cells could not.Therefore,there is an urgent need to develop more efficient computational methods of SL pairs identification for cancer targeted therapy.In this paper,we propose a new approach based on similarity fusion to predict SL pairs.Multiple types of gene similarity measures are integrated and/c-nearest neighbors algorithm(k-NN)is applied to achieve the similarity-based classification task between gene pairs.As a similarity-based method,our method demonstrated excellent performance in multiple experiments.Besides the effectiveness of our method,the ease of use and expansibility can also make our method more widely used in practice.

Emerging roles of Aurora-A kinase in cancer therapy resistance

Aurora kinase A(Aurora-A),a serine/threonine kinase,plays a pivotal role in various cellular processes,including mitotic entry,centrosome maturation and spindle formation.Overexpression or gene-amplification/mutation of Aurora-A kinase occurs in different types of cancer,including lung cancer,colorectal cancer,and breast cancer.Alteration of Aurora-A impacts multiple cancer hallmarks,especially,immortalization,energy metabolism,immune escape and cell death resistance which are involved in cancer progression and resistance.This review highlights the most recent advances in the oncogenic roles and related multiple cancer hallmarks of Aurora-A kinase-driving cancer therapy resistance,including chemoresistance(taxanes,cisplatin,cyclophosphamide),targeted therapy resistance(osimertinib,imatinib,sorafenib,etc.),endocrine therapy resistance(tamoxifen,fulvestrant) and radioresistance.Specifically,the mechanisms of Aurora-A kinase promote acquired resistance through modulating DNA damage repair,feedback activation bypass pathways,resistance to apoptosis,necroptosis and autophagy,metastasis,and stemness.Noticeably,our review also summarizes the promising synthetic lethality strategy for Aurora-A inhibitors in RB1,ARID1A and MYC gene mutation tumors,and potential synergistic strategy for m TOR,PAK1,MDM2,MEK inhibitors or PD-L1 antibodies combined with targeting Aurora-A kinase.In addition,we discuss the design and development of the novel class of Aurora-A inhibitors in precision medicine for cancer treatment.

Mutant KRAS as a critical determinant of the therapeutic response of colorectal cancer

Mutations in the KRAS oncogene represent one of the most prevalent genetic alterations in colorectal cancer(CRC),the third leading cause of cancer-related death in the US.In addition to their well-characterized function in driving tumor progression,KRAS mutations have been recognized as a critical determinant of the therapeutic response of CRC.Recent studies demonstrate that KRAS-mutant tumors are intrinsically insensitive to clinically-used epidermal growth factor receptor(EGFR)targeting antibodies,including cetuximab and panitumumab.Acquired resistance to the anti-EGFR therapy was found to be associated with enrichment of KRAS-mutant tumor cells.However,the underlying molecular mechanism of mutant-KRAS-mediated therapeutic resistance has remained unclear.Despite intensive efforts,directly targeting mutant KRAS has been largely unsuccessful.This review summarizes the recent advances in understanding the biological function of KRAS mutations in determining the therapeutic response of CRC,highlighting several recently developed agents and strategies for targeting mutant KRAS,such as synthetic lethal interactions.

Design, synthesis, and biological evaluation of quinazolin-4(3H)-one derivatives co-targeting poly (ADP-ribose) polymerase-1 and bromodomain containing protein 4 for breast cancer therapy

This study was aimed to design the first dual-target small-molecule inhibitor co-targeting poly(ADP-ribose)polymerase-1(PARP1)and bromodomain containing protein 4(BRD4),which had important cross relation in the global network of breast cancer,reflecting the synthetic lethal effect.A series of new BRD4 and PARP1 dual-target inhibitors were discovered and synthesized by fragmentbased combinatorial screening and activity assays that together led to the chemical optimization.Among these compounds,19 d was selected and exhibited micromole enzymatic potencies against BRD4 and PARP1,respectively.Compound 19 d was further shown to efficiently modulate the expression of BRD4 and PARP1.Subsequently,compound 19 d was found to induce breast cancer cell apoptosis and stimulate cell cycle arrest at G1 phase.Following pharmacokinetic studies,compound 19 d showed its antitumor activity in breast cancer susceptibility gene 1/2(BRCA1/2)wild-type MDA-MB-468 and MCF-7 xenograft models without apparent toxicity and loss of body weight.These results together demonstrated that a highly potent dual-targeted inhibitor was successfully synthesized and indicated that co-targeting of BRD4 and PARP1 based on the concept of synthetic lethality would be a promising therapeutic strategy for breast cancer.

The role of PARP1 in the DNA damage response and its application in tumor therapy

Single-strand break repair protein poly(ADP-ribose)polymerase 1(PARP1)catalyzes the poly(ADPribosyl)ation of many key proteins in vivo and thus plays important roles in multiple DNA damage response pathways,rendering it a promising target in cancer therapy.The tumor-suppressor effects of PARP inhibitors have attracted significant interest for development of novel cancer therapies.However,recent evidence indicated that the underlying mechanism of PARP inhibitors in tumor therapy is more complex than previously expected.The present review will focus on recent progress on the role of PARP1 in the DNA damage response and PARP inhibitors in cancer therapy.The emerging resistance of BRCA-deficient tumors to PARP inhibitors is also briefly discussed from the perspective of DNA damage and repair.These recent research advances will inform the selection of patient populations who can benefit from the PARP inhibitor treatment and development of effective drug combination strategies.

Recent advancements in PARP inhibitors-based targeted cancer therapy

Poly(ADP-ribose)polymerase inhibitors(PARPi)are a new class of agents with unparalleled clinical achievement for driving synthetic lethality in BRCA-deficient cancers.Recent FDA approval of PARPi has motivated clinical trials centered around the optimization of PARPi-associated therapies in a variety of BRCA-deficient cancers.This review highlights recent advancements in understanding the molecular mechanisms of PARP‘trapping’and synthetic lethality.Particular attention is placed on the potential extension of PARPi therapies from BRCA-deficient patients to populations with other homologous recombination-deficient backgrounds,and common characteristics of PARPi and non-homologous end-joining have been elucidated.The synergistic antitumor effect of combining PARPi with various immune checkpoint blockades has been explored to evaluate the potential of combination therapy in attaining greater therapeutic outcome.This has shed light onto the differing classifications of PARPi as well as the factors that result in altered PARPi activity.Lastly,acquired chemoresistance is a crucial issue for clinical application of PARPi.The molecularmechanisms underlying PARPi resistance and potential overcoming strategies are discussed.

CRISPR/Cas9 screening identifies a kinetochore-microtubule dependent mechanism for Aurora-A inhibitor resistance in breast cancer

Background:Overexpression of Aurora-A(AURKA)is a feature of breast cancer and associates with adverse prognosis.The selective Aurora-A inhibitor alisertib(MLN8237)has recently demonstrated promising antitumor responses as a single agent in various cancer types but its phase III clinical trial was reported as a failure since MLN8237 did not show an apparent effect in prolonging the survival of patients.Thus,identification of potential targets that could enhance the activity of MLN8237 would provide a rationale for drug combination to achieve better therapeutic outcome.Methods:Here,we conducted a systematic synthetic lethality CRISPR/Cas9 screening of 507 kinases using MLN8237 in breast cancer cells and identified a number of targetable kinases that displayed synthetic lethality interactions with MLN8237.Then,we performed competitive growth assays,colony formation assays,cell viability assays,apoptosis assays,and xenograft murine model to evaluate the synergistic therapeutic effects of Haspin(GSG2)depletion or inhibition with MLN8237.For mechanistic studies,immunofluorescence was used to detect the state of microtubules and the localization of Aurora-B and mitotic centromere-associated kinesin(MCAK).Results:Among the hits,we observed that Haspin depletion or inhibition marginally inhibited breast cancer cell growth but could substantially enhance the killing effects of MLN8237.Mechanistic studies showed that co-treatment with Aurora-A and Haspin inhibitors abolished the recruitment of Aurora-B and mitotic centromere-associated kinesin(MCAK)to centromeres which were associated with excessive microtubule depolymerization,kinetochore-microtubule(KT-MT)attachment failure,and severe mitotic catastrophe.We further showed that the combination of MLN8237 and the Haspin inhibitor CHR-6494 synergistically reduced breast cancer cell viability and significantly inhibited both in vitro and in vivo tumor growth.Conclusions:These findings establish Haspin as a synthetic lethal target and demonstrate CHR-6494 as a potential combinational drug for promoting the therapeutic effects of MLN8237 on breast cancer.

Comparative analysis of metabolic network of pathogens

BACKGROUND： Metabolic networks are complex and system of highly connected chemical reactions and hence it needs a system level computational approach to identify the genotype- phenotype relationship. The study of essential genes and reactions and synthetic lethality of genes and reactions plays a crucial role in explaining functional links between genes and gene function predictions. METHODS： Flux balance analysis （FBA） has been developed as a powerful method for the in silico analyses of metabolic networks. In this study, we present the comparative analysis of the genomic scale metabolic networks of the four microorganisms i.e. Salmonella typhimurium, Mycobacterium tuberculosis, Staphylococcus aureus, and Helicobacter pylori. The fluxes of all reaction were obtained and the growth rate of the organism was calculated by setting the biomass reaction as the objective function. RESULTS ＆ CONCLUSIONS： The average lethality fraction of all the four organisms studied ranged from 0.2 to 0.6. It was also observed that there are very few metabolites which are highly connected. Those metabolites that are highly connected are supposed to be the ‘global players＇ similar to the hub protein in the protein - protein interaction network.