Low testing rates and high BRCA prevalence: Poly (ADP-ribose) polymerase inhibitor use in Middle East BRCA/homologous recombination deficiency-positive cancer patients

BACKGROUND Poly(ADP-ribose)polymerase inhibitors(PARPis)are approved as first-line therapies for breast cancer gene(BRCA)-positive,human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer.They are also effective for new and recurrent ovarian cancers that are BRCA-or homologous recombination deficiency(HRD)-positive.However,data on these mutations and PARPi use in the Middle East are limited.AIM To assess BRCA/HRD prevalence and PARPi use in patients in the Middle East with breast/ovarian cancer.METHODS This was a single-center retrospective study of 57 of 472 breast cancer patients tested for BRCA mutations,and 25 of 65 ovarian cancer patients tested for HRD.These adult patients participated in at least four visits to the oncology service at our center between August 2021 and May 2023.Data were summarized using descriptive statistics and compared using counts and percentages.Response to treatment was assessed using Response Evaluation Criteria in Solid Tumors criteria.RESULTS Among the 472 breast cancer patients,12.1%underwent BRCA testing,and 38.5%of 65 ovarian cancer patients received HRD testing.Pathogenic mutations were found in 25.6%of the tested patients:26.3%breast cancers had germline BRCA(gBRCA)mutations and 24.0%ovarian cancers showed HRD.Notably,40.0%of gBRCA-positive breast cancers and 66.0%of HRD-positive ovarian cancers were Middle Eastern and Asian patients,respectively.PARPi treatment was used in 5(33.3%)gBRCA-positive breast cancer patients as first-line therapy(n=1;7-months progression-free),for maintenance(n=2;>15-months progression-free),or at later stages due to compliance issues(n=2).Four patients(66.6%)with HRD-positive ovarian cancer received PARPi and all remained progression-free.CONCLUSION Lower testing rates but higher BRCA mutations in breast cancer were found.Ethnicity reflected United Arab Emirates demographics,with breast cancer in Middle Eastern and ovarian cancer in Asian patients.

Poly(ADP-ribose) polymerase inhibition reveals a potential mechanism to promote neuroprotection and treat neuropathic pain

Neuropathic pain is triggered by the lesions to peripheral nerves which alter their structure and function. Neuroprotective approaches that jimit the pathological changes and improve the behavioral outcome have been well explained in different experimental models of neuropathy but translation of such strategies to clinics has been disappointing. Experimental evidences revealed the role of free radicals, especially per- oxynitrite after the nerve injury. They provoke oxidative DNA damage and consequent over-activation of the poly（ADP-ribose） polymerase （PARP） upregulates pro-inflammatory pathways, causing bioenergetic crisis and neuronal death. Along with these changes, it causes mitochondrial dysfunction leading to neu- ronal apoptosis. In related preclinical studies agents that neutralize the free radicals and pharmacological inhibitors of PARP have shown benefits in treating experimental neuropathy. This article reviews the in- volvement of PARP over-activation in trauma induced neuropathy and therapeutic significance of PARP inhibitors in the experimental neuropathy and neuropathic pain.

Inhibition of poly(ADP-Ribose)polymerase:A promising strategy targeting pancreatic cancer with BRCAness phenotype

The use of chemotherapeutic regimens for the treatment of pancreatic cancer is still limited because pancreatic cancer is usually diagnosed at an advanced stage as a refractory disease in which symptoms are difficult to recognize in the early stages.Furthermore,at advanced stages,there are important challenges to achieve clinical benefit and symptom resolution,even with the use of an expanded spectrum of anticancer drugs.Recently,a point of reduced susceptibility to conventional chemotherapies by breast cancer susceptibility gene(BRCA)mutations led to a new perspective for overcoming the resistance of pancreatic cancer within the framework of increased genome instability.Poly(ADP-Ribose)polymerase(PARP)-1 is an enzyme that can regulate intrinsic functions,such as response to DNA damage.Therefore,in an environment where germline mutations in BRCAs(BRCAness)inhibit homologous recombination in DNA damage,resulting in a lack of DNA damage response,a key role of PARP-1 for the adaptation of the genome instability could be further emphasized.Here,we summarized the key functional role of PARP-1 in genomic instability of pancreatic cancer with the BRCAness phenotype and listed clinical applications and outcomes of PARP-1 inhibitors to highlight the importance of targeting PARP-1 activity.

Poly （ADP-ribose） polymerase inhibitor reduces heart ischaemia/ reperfusion injury via inflammation and Akt signalling in rats

Background Poly （ADP-ribose） polymerase （PARP） has been proposed to play an important role in the pathogenesis of heart ischaemia/reperfusion （I/R） injury. 3,4-dihydro-5-[4-（1-piperidinyl）butoxy]-l（2H）-isoquinolinone （DPQ）, a potent PARP inhibitor, has cardiac protective effects. Because the underlying mechanisms are not understood, we investigated the effect of DPQ on heart I/R injury and its mechanisms. Methods Studies were performed with I/R rats＇ hearts. DPQ was used to inhibit the activation of PARP. Cardiac function and cellular apoptosis were assessed. The activation of PARP, transcription factor nuclear factor-kappaB （NF-KB）, intercellular adhesion molecule-1 （ICAM-1）, cyclooxygenase-2 （COX-2） and matrix metalloproteinase-9 （MMP-9） were evaluated. We also evaluated expression of Akt and two of its downstream targets, glycogen synthase kinase-313 （GSK- 3β） and forkhead transcription factor FOXO3a. Results Administration of DPQ significantly decreased the activation of PARP and cellular apoptosis from （35±5）% to （20±4）% and simultaneously improved the cardiac function. DPQ reduced the expressions of NF-KB, ICAM-1, COX-2 and MMP-9 in rat heart and facilitated the activations of phosphor-Akt, phosphor-GSK-3β and phosphor-FOXO3a. Conclusion The protective effects of DPQ were associated with the suppression of inflammation and the activation of the Akt signalling pathways suggesting that the inhibition of poly （ADP-ribose） polymerase reduced heart I/R injury in rats.

Effect of the regimen of Gaoshan Hongjingtian on the mechanism of poly（ADP-ribose） polymerase regulation of nuclear factor kappa B in the experimental diabetic retinopathy

Background Poly（ADP-ribose） polymerase （PARP） plays an important role in the death of retinal capillary cells in diabetic retinopathy （DR） partly via its regulation of nuclear factor kappa B （NF-κB）. The current study investigated the effect of the regimen of Gaoshan Hongjingtian （RG） on the mechanism of PARP regulation of NF-κB, and demonstrated the possible impact of the RG and Gaoshan Hongjingtian （Rhodiola sachalinensis, RS） on diabetic retinopathy. Methods Wistar rats were made diabetic by administering streptozotocin. They were then assigned to three groups at random. After 2 months, the three groups of these diabetic rats were treated with RS or RG, or untreated. Analyses of expression levels of PARP, NF-κB, and intercellular adhesion molecule-1 （ICAM-1） in the retinas of rats in different groups were performed by Western blotting and immunohistochemical assays, and mRNA levels of NF-κB and ICAM-1 were determined by real-time polymerase chain reaction （PCR）. In addition, the basement membranes of capillaries in the rats＇ retinas were observed using electron microscopy, and diabetes-induced capillary degeneration （ghost pericytes and acellular capillaries） were quantitated. Results From the third month after the injection of streptozotocin, the diabetic rats were given daily RG, RS or tap water separately. The diabetic rats failed to gain weight compared with normal age-matched rats, whereas their glycated hemoglobin levels were significantly increased. After 5 months, the mRNA levels of NF-KB and ICAM-1 and the protein expression of PARP, NF-κB, and ICAM-1 were significantly increased in the retinas of diabetic rats in the untreated group compared with the nondiabetic controls. After 8 months, the number of degenerated retinal capillaries （ghost pericytes and acellular capillaries） was significantly increased in the diabetic rats in the untreated group compared with normal age-matched rats. RG and RS inhibited diabetes-induced over-expression of PARP, NF-KB, and ICAM-1 in the retinas of diabetic rats at the end of 5-month diabetic duration. Treatment using RG and RS significantly inhibited increases in the number of acellular capillaries and pericyte ghosts and suppressed the basement membrane thickening in the retinas of rats with diabetes for 8 months compared with the control diabetic rats. Conclusions These results indicate that PARP plays an important role in the pathogenesis of diabetic retinopathy. RS and RG may have acted on the mechanism of PARP regulation of NF-κB, which suppressed the expression of NF-KB and ICAM-1, and led to the inhibition of retinal capillary degeneration.

Assaying poly(ADP-ribose) polymerase activity in plants by polarographic method

A new method has been developed to assay poly(ADP-ribose) polymerase (PARP) activity in plant tissues through determining the content of nicotinamide (NIC) produced by enzymatic reaction by linear sweeping polarographic method. The detection limit of NIC was 0.03μmol/L, the calibration graph was linear up to 5μmol/L ( r = 0.999). The recoveries were approximately in the range of 92% to 98% and the relative standard deviations were less

Association of poly(ADP-ribose) polymerase activity in circulating mononuclear cells with myocardial dysfunction in patients with septic shock

Background Severe sepsis and septic shock are the leading causes of morbidity and mortality in hospitalized patients.This study aimed to investigate the association of poly（ADP-ribose） polymerase-1 （PARP-1） activity in circulating mononuclear cells with myocardial dysfunction in patients with septic shock.Methods A total of 64 patients with septic shock were divided into the survival group （n=41） and the nonsurvival group （n=23） according to mortality at 28 days after enrollments.PARP-1 activity in circulating mononuclear cells,brain natriuretic peptide,Acute Physiology and Chronic Health Evaluation Ⅱ score,the cardiac index （CI）,the cardiac function index （CFI）,global ejection fraction （GEF）,and the left ventricular contractility index （dp/dt max） were measured after admission to the intensive care unit.Results PARP-1 activity in circulating mononuclear cells of nonsurvival patients with septic shock was significantly higher than that in survival patients.PARP-1 activity in circulating mononuclear cells was strongly,negatively correlated with the CI,the CFI,GEE and dp/dt max.Multiple Logistic regression analysis showed that PARP-1 activity in circulating mononuclear cells was an independent risk factor of myocardial dysfunction.The optimal cutoff point of PARP-1 activity for predicting 28-day mortality was 942 nmol/L with a sensibility of 78.2% and specificity of 65.1%.Conclusion PARP-1 activity in circulating mononuclear cells is significantly associated with myocardial dysfunction and may have prognostic value in patients with septic shock.

Effects of 3-aminobenzamide on poly(ADP-ribose)polymerase expression,apoptosis and cell cycle progression of HeLa cells after X-ray irradiation

The aim of this paper is to study the changes of apoptosis and cell cycle progression in HeLa cells after the poly(ADP-ribose)polymerase(PARP)was inhibited by its inhibitor 3-aminobenzamide(3-AB)and the mechan-isms of PARP action on HeLa cells damaged by irra-diation.Flow cytometry(FCM)was used to examine the PARP expression and the percentage of apoptotic cells and cell cycle progression.The percentage of HeLa cells with positive expression of PARP protein 2,4,8 and 12 h after administrated with 3-AB was significantly lower than that of the control(P<0.01).The percentages of apoptotic cells in the 3-AB plus irradiation group at the time points of 2,8,12 and 24 h after 2 Gy irradiation were higher than that in the irradiation group(P<0.01 or P<0.05)and the percentage of G2 cells decreased signifi-cantly(P<0.01 or P<0.05).It indicates that 3-AB can rapidly inhibit PARP expression of HeLa cells,promote cell apoptosis and block G2 arrest induced by irradiation.

Mechanisms of acquired resistance of BRCA1/2-driven tumors to platinum compounds and PARP inhibitors

Molecular pathogenesis of tumors arising in BRCA1/2 germ-line mutation carriers usually includes somatic inactivation of the remaining allele of the involved gene.Consequently,BRCA1/2-driven cancers are sensitive to platinum-based therapy and poly(ADP-ribose)polymerase inhibitors(PARPi).Long-term exposure to these drugs may result in the emergence of secondary BRCA1/2 mutations,which restore the open-reading frame of the affected allele.This platinum/PARPi crossresistance mechanism applies both for BRCA1 and BRCA2 genes and has been repeatedly validated in various laboratory models and multiple clinical studies.There are some other routes associated with the partial rescue of BRCA1/2 function or the development of BRCA1/2-independent pathways for genomic maintenance;however,their actual clinical relevance remains to be established.In addition,studies on the short-term neoadjuvant therapy for ovarian cancer revealed that even chemonaive BRCA1-driven tumors contain a small proportion of BRCA1-proficient cells.These pre-existing cells with retained BRCA1 heterozygosity rapidly repopulate the tumor mass during platinum exposure,but become outcompeted by BRCA1-deficient cells during therapy holidays.Understanding of the platinum/PARPi resistance pathways has led to the development of novel therapeutic approaches,which aim to improve the management of BRCA1/2-related cancers and are currently undergoing preclinical and clinical evaluation.

PARP inhibitor reduces proliferation and increases apoptosis in breast cancer cells

Objective： Apoptosis is a reliable marker of chemotherapeutic efficacy. Olaparib and paclitaxel inhibit proliferation and induce apoptosis in a variety of cancers. We investigated the effects of paclitaxel combined with olaparib on apoptosis in breast cancer Bcap37 cells. Methods： Proliferation and apoptosis were detected by MTT assay and PI staining. Degradation of procaspase-3 and poly（ADP-ribose） polymerase （PARP） was analyzed by Western blotting. Results： Compared with paclitaxel alone, paclitaxel combined with 100 mg olaparib significantly reduced survival in Bcap37 cells at all tested treatment durations （P〈0.05）; inhibition increased with increasing olaparib dose and treatment time （P〈0.01）. Combined treatment yielded significantly higher rates of apoptosis （P〈0.05）, which also increased with time （P〈0.01）. Fluorescence micrographs showed that early and late apoptotic cells increased with treatment time. Pro-caspase-3 and PARP degradation was induced by paclitaxel and enhanced by olaparib in a dose-dependent manner. Thus, combined treatment was substantially more effective than treatment with paclitaxel alone. Conclusions： Our findings suggest that paclitaxel and olaparib inhibit breast cancer Bcap37 cell proliferation and induce apoptosis. Combined treatment further reduced cell growth and enhanced apoptosis, suggesting that this combination therapy may be a promising treaunent for breast cancer.

Combining PD1 inhibitor,PARP inhibitor and antiangiogenic medication for lung squamous cell carcinoma with liver metastasis:a case report

A 68-year-old man with left chest pain accompanied by chest tightness was reported.The computed tomography revealed a massive liver mass.Genetic and pathological tests confirmed advanced squamous cell lung carcinoma with the mutation of breast cancer susceptibility gene 1 and liver metastasis.The primary lung lesions and local liver metastases were well controlled through combined immunotherapy,antiangiogenic medications and Poly ADP-ribose polymerase inhibitors.Considering the high tumor load and the generally poor condition of the patient,transarterial chemoembolization,in place of the conventional chemotherapy treatment mode was chosed for liver metastasis in the current case.We discussed selecting a tailored program and outlined the patient’s diagnosis and treatment process.Additionally mentioned multiple drug combination strategies for squamous lung cancer.

PARP抑制剂与免疫检查点抑制剂联合治疗在妇科恶性肿瘤中的应用

近年来肿瘤靶向和免疫治疗的研究进展迅速,如多腺苷二磷酸核糖聚合酶抑制剂[poly(ADP-ribose)polymerase inhibitor,PARPi]、免疫检查点抑制剂(immune checkpoint inhibitors,ICI)等已改变了妇科肿瘤的传统治疗模式,但部分患者疗效有限或出现耐药。临床前研究发现,PARPi损伤DNA修复过程,可造成肿瘤突变负荷与肿瘤特异性抗原增加,调节肿瘤微环境,刺激肿瘤浸润淋巴细胞(tumor infiltrating lymphocytes,TIL)产生并促进抗肿瘤免疫反应,为PARPi与ICI联合治疗提供了理论基础。近年多项临床研究发现PARPi与ICI联合使用可显著改善妇科恶性肿瘤患者的预后。

PARP抑制剂Olaparib对非小细胞肺癌细胞的放疗增敏作用及其机制

目的探讨聚腺苷二磷酸核糖聚合酶(PARP)抑制剂Olaparib对人非小细胞肺癌(NSCLC)细胞的放疗增敏作用及其可能的发生机制。方法以人NSCLC细胞A549细胞系为研究对象,采用CCK-8实验检测不同药物浓度梯度对细胞的增殖抑制作用。选择对细胞10%抑制浓度(IC10)作为后续实验的药物浓度,实验分为对照组、Olaparib组、单纯放疗组(RT组)、Olaparib联合放疗组(Olaparib+RT组)。通过克隆形成实验和EDU细胞增殖实验检测Olaparib联合放疗后的增敏效果,流式细胞术检测各组细胞周期分布,Western blot实验检测各组DNA损伤标志蛋白γ-H2AX的表达。结果Olaparib对A549细胞具有抑制作用且呈剂量依赖性;在处理A549细胞24 h后IC10为2.593μmol·L^(-1);Olaparib放疗增敏比为1.966。Olaparib+RT组A549细胞的增殖能力下降(P<0.01);Olaparib+RT组的G2/M期细胞占比高于对照组(46.0%vs 10.8%,P<0.05);且Olaparib+RT组细胞中γ-H2AX明显高于RT组(P<0.01)。结论Olaparib对人NSCLC细胞A549细胞系有着放疗增敏效果,其机制可能与影响细胞周期、增加放疗后细胞DNA双链断裂形成相关。

PARP抑制剂治疗转移性去势抵抗性前列腺癌有效性及安全性的Meta分析

目的:系统评价PARPi治疗转移性去势抵抗性前列腺癌(mCRPC)的有效性及安全性,以期为临床决策供循证医学证据。方法:依据纳入和排除标准,网络检索2015年1月~2023年6月PubMed、Web of Science、Embace、Clinicial.gov中有关PARPi治疗mCRPC的随机对照试验文献,使用RevMan5.4及Stata17.0软件对数据进行Meta分析。结果:纳入7篇随机对照试验文献,共1888例患者。Meta分析结果表明,与非PARPi组比较,PARPi组(PARPi联合或不联合抗激素治疗)可提高mCRPC的放射学无进展生存期(HR=0.52,95%CI=0.34~0.78)和总生存期(HR=0.72,95%CI=0.60~0.86),差异均有统计学意义(P<0.05)。在安全性方面,PARPi组1~2级骨痛、背痛、贫血、中性粒细胞减少、恶心、呕吐、腹泻、乏力不良反应发生率明显高于非PARPi组,差异均有统计学意义(P<0.05);≥3级上述不良反应中与非PARPi组比较,PARPi组中只有恶心和贫血不良反应发生率较高,差异均有统计学意义(P<0.05),而骨痛、背痛、中性粒细胞减少、呕吐、腹泻、乏力两组间比较差异均无统计学意义(P>0.05)。结论:与非PARPi比较,PARPi联合或不联合抗激素治疗可提高mCRPC的放射学无进展生存期和总生存期,3级及以上不良反应发生率低,值得在临床上推广应用。

同源重组修复缺陷检测国家参考品

目的制备同源重组修复缺陷检测(HRD)国家参考品,并建立其标准集,用于HRD体外诊断试剂产品的性能评价。方法采用肿瘤组织永生化的细胞和配对白细胞永生化的细胞,制备不同DNA比例(50%,40%,30%,20%,10%)的HRD国家参考品。将其基因组DNA打断,进行全外显子测序(WES),将获得的测序数据进行分析。首先合并拷贝数变异(CNV)检测大于10 Mb区域,构建成区间树。然后将区间树拆分成最小节点,统计各节点检出频次及节点中各类型检出频次,建立等位基因特异性拷贝数(ASCNV)标准集。使用scarHRD软件建立LOH、LST及TAI标准集。结果ASCNV标准集包括节点检出频率≥50%的节点,且节点合并后长度≥3 Mb。建立了国家参考品的LOH、LST及TAI三个指标的标准集。结论HRD国家参考品和标准集,可以为同源重组修复缺陷检测试剂盒的性能评价提供技术支撑。

Sitravatinib联合Niraparib对黏膜黑色素瘤细胞系增殖、凋亡和自噬的影响及其机制

目的研究抗血管生成药物Sitravatinib联合多聚(腺苷二磷酸[ADP]-核糖)聚合酶抑制剂(PARPi)Niraparib对黏膜黑色素瘤细胞的作用及其可能的机制。方法CCK8法检测Sitravatinib和Niraparib在黏膜黑色素瘤(MM)细胞系的半数抑制浓度(IC 50);CompuSyn模型计算不同浓度联合条件下的联合指数(CI)。细胞集落形成实验测定细胞增殖;流式细胞测量术测定细胞凋亡;Western blot检测蛋白质表达;RT-qPCR检测mRNA表达。结果在人阴道黏膜来源黑色素瘤细胞系(HMVⅡ)和人外阴黏膜黑色素瘤腹股沟淋巴结转移病灶来源细胞系(GAK)中Sitravatinib(2μmol/L)联合Niraparib(20μmol/L)条件下CI值分别为0.19和0.15;与对照组及单药组相比,联合组细胞增殖能力显著下降(P<0.05或P<0.01或P<0.001);细胞凋亡率显著升高(P<0.01或P<0.001),凋亡标志物蛋白质和mRNA表达均显著升高(P<0.001);细胞自噬标志物蛋白质和mRNA表达显著升高(P<0.01或P<0.001);DNA损伤相关蛋白质表达显著升高。而与对照组相比,Sitravatinib单药组和联合组重组酶辐射敏感蛋白51(RAD51)表达显著下降。随着Sitravatinib剂量逐渐升高至2μmol/L,RAD51蛋白和mRNA表达显著下降(P<0.05或P<0.01),BRCA1与BRCA2的mRNA表达显著下降(P<0.05或P<0.01或P<0.001)。结论Sitravatinib联合Niraparib可抑制黏膜黑色素瘤细胞增殖,诱导细胞凋亡并促进细胞自噬,其机制可能与Sitravatinib抑制同源重组修复(HRR)水平相关。

铂敏感复发性卵巢癌维持治疗药物的研究进展

卵巢癌是一种严重威胁女性生命健康的疾病,经过规范治疗后仍有超过70%的患者复发,而复发性卵巢癌无法治愈。复发性卵巢癌的经典分类方法是根据复发时距末次含铂化疗的时间间隔,分为铂敏感、铂耐药及铂难治,其中对于铂敏感复发性卵巢癌应用维持性治疗是降低复发风险或延缓复发的重要手段。本文就目前广泛应用于铂敏感复发性卵巢癌维持治疗药物的研究进展予以综述,如抗血管生成药物、聚腺苷二磷酸聚合酶抑制剂、免疫检查点抑制剂等。

Effects of 3-aminobenzamide on expressions of poly（ADP ribose） polymerase and apoptosis inducing factor in cardiomyocytes of rats with acute myocardial infarction

Background Poly（ADP-ribose） polymerase （PARP） plays an important role in cell survival and death. However, the mechanisms involved are not fully understood. Therefore, we investigated the effect of inhibition of PARP on acute myocardial infarction （AMI） at different time points in rats. Methods AMI was induced in rats by ligating the left anterior descending coronary artery. One group received 3-aminobenzamide （3-AB, a kind of PARP inhibitor） （30 mg/kg） by intraperitoneal injection. The changes of ultramicrostructure of cardiocytes in infarction region were noted, PARP cleavage was measured by Western blotting, and expressions of protein of PARP and apoptosis inducing factor （AIF） were measured by immunohistochemical staining after treatment with 3-AB for 2 hours, 4 hours, 6 hours, 1 week, 4 weeks and 8 weeks. Results Few damages to the ultramicrostructure of cardiocytes were observed after treatment with 3-AB. PARP cleavage was detected as early as 4 hours and markedly increased by 6 hours following AMI without 3-AB, but was not found until 6 hours following AMI treated with 3-AB. There were significant differences between 3-AB and AMI groups at the same time points. The expression of PARP was observed gradually increased, but that of AIF was suppressed for 6 hours after treatment of 3-AB, compared with AMI groups in positive cells at the same time points. There was significantly less cleavage of PARP and more PARP expression in 3-AB treated group compared with AMI and control groups at all matched time points. Conclusions Our results suggest that 3-AB inhibits degradation of PARP, increases the expression of PARP protein, and suppresses the expression of AIF protein. Inhibition of PARP activity may protect cardiocytes in rats with AMI and reduce apoptosis.

PARP抑制剂在上皮性卵巢癌中的耐药机制及解决策略

上皮性卵巢癌(epithelial ovarian cancer,EOC)的致死率在女性生殖系统恶性肿瘤中居首位。EOC的传统治疗方案是肿瘤细胞减灭术联合铂类药物为基础的化疗,但2年内仍有约70%的患者复发或耐药。多腺苷二磷酸核糖聚合酶[poly(ADP-ribose)polymerase,PARP]抑制剂通过对乳腺癌相关基因(breast cancer-related gene,BRCA)突变的肿瘤细胞发挥合成致死效应,为EOC提供了全新的治疗模式。PARP抑制剂为EOC靶向维持治疗带来重大突破,然而仍有患者在治疗中逐步耐药,主要的耐药机制包括同源重组修复途径恢复、药物靶点变化和致死性DNA损伤减少,目前的解决策略包括PARP抑制剂联合DNA损伤修复抑制剂、联合抑制同源重组修复通路的药物、联合传统抗癌方案、联合P-糖蛋白(P-glucoprotein,P-gp)抑制剂以及更换其他类型的PARP抑制剂。