摘要
聚腺苷二磷酸核糖聚合酶-1(PARP-1)在生物体中发挥着强大的生理功能,包括DNA损伤修复,维持基因组稳定性,调节细胞增殖、分化、死亡,等。目前PARP抑制剂在乳腺癌易感基因BRCA1/2突变的肿瘤如乳腺癌、卵巢癌、前列腺癌和胰腺癌中得到了广泛应用。但对于其他恶性肿瘤以及对PARP抑制剂产生耐药的人群,PARP抑制剂有一定的局限性。本文通过分析总结PARP抑制剂在肺癌、肝细胞癌、胶质母细胞瘤、白血病及宫颈癌中的临床前及临床研究进展,同时针对PARP抑制剂耐药情况,总结其与其他抗肿瘤药物如DNA损伤修复抑制剂、免疫检查点抑制剂、抗血管生成药物以及其他化疗药物联用解决耐药的策略,为未来PARP抑制剂的临床应用提供参考依据。
聚腺苷二磷酸核糖聚合酶(poly ADP-ribose polymerase,PARP)是一类将ADP-核糖基团转移至靶标蛋白从而影响各种细胞过程的蛋白质超家族,由17种酶构成,它们在维持基因组稳定性和调节信号通路等方面发挥着不可替代的作用。其中PARP-1在细胞中表达高且响应快,能快速催化并修饰DNA修复因子,与它们相互作用参与各种DNA修复过程。因此针对DNA损伤修复缺陷的肿瘤细胞,PARP抑制剂应运而生。PARP抑制剂的主要作用机制有两种:(1)合成致死效应:PARP-1识别并修复DNA单链断裂(single-strand breakage,SSB)损伤,结合并捕获在断裂的DNA上,引起DNA单链损伤积累,导致更严重的DNA双链断裂(double-strand breakage,DSB),断裂的双链可以通过同源重组修复(homologous recombination repair,HRR),但在BRCA1/2突变后HRR途径受到抑制,DNA损伤得不到修复,最终导致细胞死亡。(2)PARP-DNA捕获理论:PARP抑制剂将PARP-1蛋白捕获在DNA上,长期存在的PARP-DNA复合物占据DNA损伤位点,导致细胞停滞在S期,PARP捕获的DNA不断积累,造成了毒性更强的DSB损伤,干扰DNA复制,导致复制叉的停滞和后续的双链DNA损伤,从而引起细胞死
迄今为止,PARP抑制剂在伴有BRCA1/2突变的实体瘤中进行了广泛的研究,并被批准用于卵巢癌、乳腺癌、前列腺癌和胰腺癌。目前美国食品药品监督管理局(FDA)批准的PARP抑制剂有奥拉帕利(olaparib)、尼拉帕利(niraparib)、卢卡帕利(rucaparib)和他拉唑帕利(talazoparib)。获批情况见
BRCA为乳腺癌易感基因;HRD为同源重组缺陷;HRR为同源重组修复;HER2为人表皮生长因子受体2
PARP抑制剂利用合成致死效应形成DNA双链损伤,HRR是DNA双链损伤的重要修复方式,起作用的关键蛋白是BRCA1和BRCA2,如果肿瘤细胞HRR功能异常(如BRCA突变),就会引起肿瘤细胞死亡。其他HRR相关基因(如RAD51、ATM、PALB2、MRE11、CHEK2等)发生突变、或BRCA基因启动子甲基化以及其他原因都会引起HRR功能异常(homologous recombination deficiency,HRD),因此在使用PARP抑制剂之前,有必要对患者进行HRD检测。HRD检测是针对HRR相关基因的检测,BRCA突变只是导致HRD的原因之一,虽然BRCA1/2突变是首选的PARP抑制剂敏感生物标志
癌 在常见恶性肿瘤中,肺癌的发病率和病死率均居首位。小细胞肺癌(small cell lung cancer,SCLC)主要与吸烟有关,约占所有肺癌的10% ~ 15%。SCLC基因组普遍存在TP53和RB1失活,这使肿瘤细胞更加依赖DNA损伤修复。研究发现SCLC中PARP-1表达高且对铂类化疗敏
表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)耐药已成为晚期肺癌的主要挑战。研究表明PARP-1在TKI敏感细胞中的表达低于抗性细胞,且TKI耐药细胞对PARP抑制剂的敏感性显著高于TKI敏感细胞,这在7 ~ 8个患者来源的肿瘤细胞中得到了验
肝细胞癌(hepatocellular carcinoma,HCC)系原发性肝癌最为典型的病理学分型之一,约占原发性肝癌的85% ~ 90%,其发生率世界排名第6位,致死率排名第4位。研究表明HRD与肝细胞癌的发生发展存在密切的关系。在分析27名HCC患者PARP-1表达差异时发现与非癌组织相比,癌组织中的PARP-1蛋白显著增加,且在分化程度较低的肿瘤中PARP-1的表达更
索拉菲尼(sorafenib)被FDA批准为晚期HCC的一线治疗药物。然而耐药性的发展通常会阻碍其长期疗效。研究发现在异种移植小鼠模型中用索拉菲尼治疗后,PARP-1被激活并通过维持“开放染色质”结构来促进DNA损伤修复。这导致肝癌细胞对索拉菲尼产生抗性。体内外实验也证实奥拉帕利和尼拉帕利可显著增加索拉菲尼的疗
胶质母细胞瘤(glioblastoma multiforme,GBM)是最常见的侵袭性原发性恶性脑肿瘤,目前治疗主要包括手术切除后放疗和化疗。然而中位生存期仅略微延长,且复发肿瘤在数月内就会出现。研究发现PARP-1在GBM中过表达,且PARP-1的表达水平与肿瘤分级呈正相关,与患者存活率呈负相
错配修复(mismatch repair,MMR)缺陷的出现是GBM对化疗药物替莫唑胺产生获得性耐药的常见机制。研究发现不依赖于O-6-甲基鸟嘌呤DNA甲基转移酶(O-6-methylguanine DNA methyltranferase,MGMT)和PTEN,替莫唑胺联合PARP抑制剂可用于克服化疗药物获得性耐药
急性髓细胞白血病(acute myeloid leukemia,AML)是一种具有遗传多样性和侵袭性的血液恶性肿瘤。近年来不断有揭示白血病发生的分子机制,虽然在白血病中与DNA损伤修复相关的基因组突变频率较
宫颈癌(cervical cancer,CC)是常见的导致女性患癌死亡的癌种。研究发现CC中信号转导和转录激活因子1(signal transduction and activation of transcription 1,STAT1)可在转录和转录后水平上调节CC细胞中PARP-1的表达,使用PARP抑制剂可选择性提高抗性CC细胞对药物治疗的敏感性。GEPIA和TCGA数据库分析表明,CC中PARP-1 mRNA高于正常组织,并且PARP-1 mRNA表达水平的增加与CC患者不良预后相
PARP抑制剂虽然在恶性肿瘤的治疗中发挥重要的作用,但也不可避免地会产生耐药,这对靶向治疗造成了巨大阻碍。目前,PARP抑制剂的主要耐药机制有以下几点:(1)HRR的恢复:这是PARP抑制剂获得性耐药经典的机制之一,由于回复突变或NHEJ活性的抑制使HRR恢复,肿瘤细胞继续存活。回复突变指二次突变重新激活BRCA1/2,BRCA1/2的开放阅读框恢复,从而使其蛋白活性恢复,导致肿瘤细胞DNA损伤功能恢复,最早在被诊断患有BRCA突变的乳腺癌和卵巢癌患者中发
PARP抑制剂的功能决定了其耐药机制并不集中在靶标蛋白突变上,肿瘤细胞倾向于改变DNA损伤修复状态导致耐药。在DNA损伤修复过程中,除了PARP-1外,其他相关蛋白也参与损伤修复,如共济失调-毛细血管扩张突变蛋白(ataxia telangiectasia-mutated,ATM)被DSB招募并执行检查点信号和DNA修复;共济失调毛细血管扩张Rad3相关蛋白(ataxia telangiectasia-mutated and Rad3 related,ATR)能被复制压力激活,从而稳定和重启复制叉;细胞周期检查点激酶1/2(checkpoint kinase 1/2,ChK1/2)是在ATR和ATM下游起作用的激酶;WEE1是一种典型的检查点激酶,对有丝分裂负调节;磷脂酰肌醇3-激酶(phosphatidylinositol-3-kinase,PI3K)和细胞间质上皮转换因子(cellular-mesenchymal epithelial transition factor,c-Met)能够稳定HRR,控制DNA修复断裂。若作为单药治疗,这些靶点抑制剂的疗效取决于相关的生物学功能。由于每种抑制剂针对靶点的局限性,DNA损伤修复抑制剂之间联合治疗可能是一种可行的治疗策
CDK4/6抑制剂帕博西尼(palbociclib)能与CDK4单独结合,抑制细胞周期从G1期进入S期从而使肿瘤细胞死亡,已获FDA批准治疗晚期乳腺癌。最近研究表明,帕博西尼和奥拉帕利联用可抑制三阴性乳腺癌(triple-negative breast cancer,TNBC)生长。在奥拉帕利耐药的乳腺癌细胞中,Wnt信号通路被激活并导致奥拉帕利抗性,通过与帕博西尼联合治疗可提高奥拉帕利的疗
WEE1是丝氨酸/苏氨酸蛋白激酶家族中的一员,是DNA损伤修复通路和细胞周期相关的重要激酶。研究表明在TNBC,SCLC和胰腺癌中,PARP抑制剂与WEE1抑制剂联用可增加治疗效果,减轻WEE1抑制剂的毒性作
ATR是磷脂酰肌醇3-激酶相关激酶蛋白家族成员,被激活后可调控细胞周期阻滞、启动复制叉和修复DNA损伤等。在小鼠皮下和原位肺癌模型中发现ATR抑制剂ceralasertib联合奥拉帕利大大增强了对皮下肿瘤的疗
CHK1抑制剂prexasertib与奥拉帕利联合在HGSOC患者源性异种移植耐药模型中产生了显著的肿瘤抑制作
PI3K在肿瘤细胞的生长转移与扩散中发挥着关键作用。在GBM中发现卢卡帕利和PI3K抑制剂buparlisib同时治疗具有协同抗癌作
c-Met是受体酪氨酸激酶家族成员。c-Met信号通路激活促使肿瘤形成、侵袭和转移。研究发现c-Met可通过磷酸化PARP-1增加其酶活,从而引起乳腺癌细胞对PARP抑制剂产生抵抗。联合使用c-Met和PARP抑制剂可以协同阻止乳腺癌细胞的生长,在小鼠的肺癌模型中也有一致的效
目前研究发现的免疫检查点有程序性死亡蛋白-1(programmed cell death protein-1,PD-1)、程序性死亡配体-1(programmed death ligand-1,PD-L1)以及细胞毒性T淋巴细胞相关抗原-4(cytotoxic tlymphocyte associated antigen-4,CTLA-4)。针对这些靶点设计的免疫检查点抑制剂能够激活肿瘤免疫应答反应,实现抗肿瘤作用。研究发现尼拉帕利可上调卵巢癌细胞表面PD-L1的表达,增强CD
血管内皮生长因子(vascular endothelial growth factor,VEGF)具有促进血管新生和再生的功能。VEGFR抑制剂通过抑制肿瘤细胞的血管生成,减少肿瘤细胞的营养获取,最终达到治疗目的。研究发现VEGFR3抑制剂能够诱导HRR相关蛋白质BRCA1/2和RAD51的下调,对增强PARP抑制剂的敏感性具有潜在价值,因此联合VEGFR抑制剂和PARP抑制剂治疗成为一种选择。在卵巢癌异种移植瘤中发现VEGFR抑制剂西地尼布(cediranib)能够增加奥拉帕利的敏感性,且这种作用和BRCA状态无
大多数化疗药物的作用机制是直接或间接损伤DNA链从而杀伤肿瘤细胞,大量临床前数据表明PARP抑制剂联用化疗药物具有协同增效的作用。PARP抑制剂与烷化剂替莫唑胺或卡铂联合治疗实体瘤的临床前研究已有很多,临床试验也相继开
作为一种新型抗肿瘤药物,PARP抑制剂一方面在HRD的肿瘤治疗中起着重要的作用,另一方面,针对PARP抑制剂治疗局限性,采用PARP抑制剂与其他抗肿瘤药物联合应用也表现出良好的疗效,但PARP抑制剂仍面临着重大的挑战:(1)联合用药的安全性:在联用其他药物克服耐药性的同时,如何在保证疗效的同时减轻不良反应。(2)HRD检测手段:除了HRR基因突变检测和基因瘢痕检测,能否研究其他精确高效的手段或工具检测HRR相关基因的突变,降低患者检测成本。(3)PARP抑制剂敏感的生物标志物:随着PARP抑制剂临床研究及临床前研究的不断进行,有必要筛选出针对PARP抑制剂敏感的生物标志物。通过分析血液,尿液,粪便和肿瘤组织样本,确定对PARP抑制剂敏感的生物标志物,有利于实验精准治疗。这个艰巨的任务需要密切的多学科合作,才能最终应用于临床实践。(4)PARP抑制剂在其他癌种中的应用:目前PARP抑制剂在乳腺癌、卵巢癌、前列腺癌和胰腺癌中得到了广泛应用,这基于PARP1的合成致死效应。是否能从其他方面如PARP1对增殖、免疫、侵袭转移等的影响来探讨PARP抑制剂在其他非HRD癌种中应用的合理性值得思考。总之,PARP抑制剂有望给更多的恶性肿瘤患者带来希望。
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