2024, Vol. 44
2. 山西医科大学第一医院医学影像科，太原 030001
2. Department of Medical Imaging, First Hospital of Shanxi Medical University, Taiyuan 030001, China
近年来恶性肿瘤的发病率不断攀升，已成为仅次于心血管疾病的第二大疾病，严重威胁人类健康。根据美国癌症协会最新发布的2023年癌症统计数据，预计将有190多万例癌症新发病例和60多万死亡病例[1]。放疗与化疗是临床肿瘤治疗的重要手段，通过损伤肿瘤细胞DNA，影响细胞有丝分裂进程，从而抑制肿瘤的生长。但放化疗有时会表现出肿瘤消退缓慢甚至治疗效果不明显的情况，其很大程度上与肿瘤细胞的DNA损伤应答(DNA damage response, DDR)与修复机制有关[2]。在多种DNA修复酶的作用下，肿瘤细胞中受到损伤的DNA分子会恢复结构，从而影响治疗效果。研究表明，靶向DDR的蛋白抑制剂一方面可以阻止肿瘤细胞DNA损伤修复，造成更加严重的DNA损伤；另一方面断裂的DNA会激活机体的抗肿瘤免疫反应，从而抑制肿瘤转移和复发[3]。本综述对一些主要的DDR抑制剂联合放疗、化疗在各种肿瘤治疗中的应用进行了总结，并阐述了其联合治疗诱导由环鸟嘌呤核苷酸腺嘌呤核苷酸合成酶-干扰素基因刺激因子(cyclin guanine nucleotide adenine nucleotide synthase-interferon gene stimulator, cGAS-STING)通路介导免疫反应的机制与应用。
一、放疗、化疗抗肿瘤机制放疗是利用高能电离辐射(ionizing radiation, IR)辐照肿瘤细胞，对细胞内DNA造成损伤，从而抑制肿瘤细胞的增殖[4]。IR主要通过两种方式损伤DNA：一是可直接离子化DNA分子，导致DNA单链断裂(single strand break, SSB)或双链断裂(double strand breaks, DSBs)及碱基、糖交联等多种类型的损伤；二是高能射线间接与组织内的水发生反应生成活性氧自由基(reactive oxygen species, ROS)，如·OH、H2O+、H3O+、·O2-等。这些自由基可以与DNA结合，使DNA分子被氧化，促使细胞DNA损伤，进而诱导肿瘤细胞凋亡。
化疗作为治疗肿瘤的常用方式之一，杀伤肿瘤的机制主要包括：①利用DNA甲基化剂(包括替莫唑胺、丙卡巴肼等)产生O6-甲基鸟嘌呤(O6-methyl guanine, O6-MeG)，导致S期DNA合成过程中与胞嘧啶或胸腺嘧啶错配，随后形成DNA断裂并最终导致细胞死亡[5]。②利用拓扑异构酶(topoisomerase, TOP)切割DNA单链或双链，导致SSB和DSBs的积累，TOP抑制剂分为TOP Ⅰ抑制剂(如喜树碱、拓扑替康、伊立替康等)和TOP Ⅱ抑制剂(如阿霉素、依托泊苷等)[5]。③利用DNA交联剂，如环磷酰胺、顺铂等，通过共价偶联DNA双链体的互补链，阻断了DNA复制和转录导致细胞死亡[6]。④利用微管蛋白抑制剂，如紫杉醇、长春新碱等，稳定并加强微管蛋白的聚集，阻止微管的解聚进而抑制有丝分裂，最终抑制肿瘤生长[7]。
当放化疗单独用于肿瘤治疗时，常会产生耐受的情况，严重影响肿瘤治疗效果。而产生耐受的关键因素是肿瘤细胞固有的DNA损伤修复系统[2, 8]，如部分下咽和鼻咽癌等肿瘤患者会对放疗产生抵抗从而影响治疗效果，这与肿瘤细胞中同源性重组(homologous recombination, HR)修复因子BRCA1、BRCA2、RAD51等过表达有关[9-10]。替莫唑胺治疗肿瘤后，其损伤的DNA会利用碱基切除修复(base excision repair, BER)等机制修复，从而使得肿瘤细胞对此药物产生耐药性[11]。而DDR抑制剂的加入有望解决由DNA损伤修复引起的放疗抗性和化疗耐药性，从而提高肿瘤治疗效果。
二、DDR抑制剂联合放疗、化疗在肿瘤治疗中的应用DDR是一个涉及DNA损伤监测、细胞周期检查点调节、DDR因子招募、染色质重组、DNA加工和修复的协同过程[12](图 1)。在肿瘤放化疗过程中，损伤的DNA触发DDR，进而促进肿瘤细胞的损伤修复，使得肿瘤细胞耐受。因此，抑制DDR相关调节因子可抑制DNA损伤修复，从而有效增强肿瘤治疗效果。近年来，研究者开发了以聚ADP-核糖聚合酶(poly ADP-ribose polymerase, PARP)、DNA依赖性激酶(DNA-dependent protein kinase, DNA-PK)、共济失调毛细血管扩张突变蛋白(ataxia telangiectasia mutated, ATM)、共济失调毛细血管扩张和Rad-3相关蛋白(ATM-related and Rad3-related, ATR)等靶点的DDR抑制剂用于肿瘤治疗，其联合放疗、化疗取得了良好的肿瘤治疗效果[5, 13-14]。
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注：RPA.复制蛋白A；ATRIP.ATR相互作用蛋白；ERGIC.内质网-高尔基体中间体；Golgi.高尔基体；TBK1.TANK结合激酶1；IFNAR.干扰素α/β受体；DC.树突状细胞 图 1 DNA损伤修复通路与损伤DNA诱导的抗肿瘤免疫反应 Figure 1 DNA damage repair pathway and anti-tumor immune response induced by damaged DNA |
1、PARP抑制剂
PARP是一种DNA修复酶[15]，PARP抑制剂是第一种利用合成致死获得批准在临床使用的抗肿瘤药[16-17]。在响应DNA损伤修复时，DNA依赖性PARP1可以快速识别SSB DNA末端并进行DDR因子的早期募集，促进染色质重塑以进行DNA修复[18]。现已开发了多种PARP抑制剂，如奥拉帕尼(olaparib, AZD2281)、维利帕尼(veliparib, ABT-888)、他拉唑帕尼(talazoparib, BMN673)、尼拉帕尼(niraparib, MK4827)、AZD2461等，其联合放疗、化疗在多种肿瘤治疗过程中展现出了良好的前景[19-20]。研究发现，PARP抑制剂可以增强放疗诱导的肿瘤细胞中ROS的水平[21]，且增强了肺癌、肝癌、卵巢癌等肿瘤细胞的放射敏感性[22-25]。PARP抑制剂联合IR治疗肿瘤临床进展见表 1。同时，PARP抑制剂联合顺铂可导致持续的DNA双链断裂，延长G2/M细胞周期阻滞，增强对非小细胞肺癌的杀伤作用[26]。在成人难治性实体瘤和淋巴瘤的Ⅰ期研究中，维利帕尼联合拓扑替康可以导致循环肿瘤细胞和外周血单核细胞中γ-H2AX增加[27]。
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表 1 DDR抑制剂联合放疗在肿瘤治疗中的临床试验 Table 1 Clinical trials of DDR inhibitor with radiotherapy in tumor treatment |
2、DNA-PK抑制剂
DNA-PK是一种丝氨酸/苏氨酸蛋白激酶，由一个大催化亚基(DNA-PKcs)和一个异二聚体DNA靶向亚基KU组成。DNA-PK在DSBs末端的组装为募集Artemis、DNA连接酶Ⅳ等参与末端加工和非同源末端连接(non-homologous end joining, NHEJ)的因子提供了平台。DNA-PKcs是磷脂酰肌醇3激酶相关激酶(phosphoinositide-3-kinase-related kinase, PIKK)家族的成员，它的自磷酸化发生在整个激酶的许多丝氨酸/苏氨酸残基上，并已被证明通过介导NHEJ在DSBs修复中起着重要作用[28]。目前所研究的DNA-PK抑制剂包括NU7441、NU7026、VX-984、SU11752、AZD7648、M3814和CC-115等，它们在联合放疗、化疗对肿瘤的治疗中展现出良好的前景[29]。研究表明，CC-115联合IR增强了黑色素瘤细胞的放射敏感性，而对正常细胞没有影响[30]，NU7441增强了依托泊苷在人结肠癌异种移植模型中的抗肿瘤活性[31]。多西环素(doxycycline)是一种具有口服活性的四环素抗生素，除了具有抗菌活性外，多西环素是美国食品和药物管理局(FDA) 批准的第一个DNA-PK抑制剂，可显著降低DNA-PK蛋白活性，并在乳腺癌细胞中充当放疗增敏剂[32]。
3、ATM抑制剂ATM在DSBs损伤修复中起着重要的作用。ATM是PIKK家族的一员，DSBs发生后，ATM由DNA修复因子MRE11-RAD50-NBS1 (MRN)复合体招募和激活, 随后ATM激活检查点激酶2(checkpoint kinase 2, CHK2)并磷酸化多个位点，介导G1期阻滞并启动DDR途径，从而介导HR修复[33]。ATM的抑制放大了肿瘤细胞的DSBs效应并阻断修复途径。已有大量的ATM抑制剂被开发出来用于肿瘤治疗，包括KU-55933、KU-60019、AZ32、AZD0156、AZD1390、GSK63541A和咖啡因等[34]。Carruthers等[35]证实KU-55933联合IR可以抑制肿瘤细胞的DSBs损伤修复，并有效增强了胶质母细胞瘤中肿瘤干细胞的放射敏感性。Scheper等[36]证实AZD0156在所有黑色素瘤细胞中具有明显的放疗增敏作用，但对健康成纤维细胞没有影响。利鲁唑作为一种治疗肌萎缩性侧索硬化症的药物，通过激活ATM/p53通路直接参与了IR诱导的鼻咽癌细胞凋亡。且因其可接受的不良反应，在鼻咽癌放射治疗中表现出良好的应用前景[37]。同时，有研究表明ATM抑制剂也可以抑制IR诱导的人肿瘤细胞系中的表皮生长因子受体(epidermal growth factor receptor, EGFR)激活，使其在EGFR替代治疗中具有潜力[38]。在联合化疗药物的实验中，KU-55933联合依托泊苷、阿霉素和喜树碱可以通过增加DSBs增强多种肿瘤细胞的化疗效果[39]。
4、ATR抑制剂ATR是DDR过程中的关键激酶，负责感知复制应激(replication stress, RS)并将其信号传递到S和G2/M检查点以促进DNA损伤修复[40]。与前面提到的DNA-PK、ATM一样，ATR也是PIKK家族的成员之一[41]。首先单链DNA可以激活ATR，然后活化的ATR可以磷酸化并激活检查点激酶1(checkpoint kinase 1, CHK1)，激活后的CHK1使周期蛋白25同源蛋白C(cyclin 25 homologous protein C, CDC25C)和蛋白激酶WEE1磷酸化，导致WEE1的激活和CDC25C的失活。最后，WEE1的激活和CDC25C的失活抑制周期蛋白依赖性激酶1-周期蛋白B(cyclin-dependent kinase1-cyclin B, CDK1-cyclin B)的复合物，从而使其失去活性，导致细胞周期停滞，并为DNA损伤修复提供时间[42]。由于大多数肿瘤细胞的G1检查点存在缺陷，使得其在DNA损伤后更加地依赖于S和G2/M检查点，这使得ATR成为一个具有吸引力的抗癌靶点。此外，在肿瘤组织内部乏氧的条件下，ATR更容易被激活，使得抑制ATR对实体肿瘤的治疗更有意义[43]。gartisertib (M4344, VX-803)、elimusertib (BAY1895344)、berzosertib (VX-970, VE-822, M6620)、ceralasertib (AZD6738)、VE-821、AZ20和NU6027等已被开发作为有效的ATR抑制剂用于抗肿瘤研究，并展现出良好的前景[40]。Baschnagel等[44]研究表明，M6620在非小细胞癌细胞放射治疗中具有明显的增敏作用。Hur等[45]证实TOPⅡ抑制剂贝洛替康联合ceralasertib治疗可以协同抑制卵巢癌细胞的增殖活性。在晚期实体瘤Ⅰ期临床试验中，berzosertib联合化疗药物顺铂或者吉他西滨表现出良好的疗效[46-48]。在铂药耐受的小细胞肺癌的Ⅰ期临床试验中，berzosertib联合拓扑替康表现出化疗增敏作用[49]。
5、其他DNA损伤修复抑制剂还有很多修复途径上的分子如WEE1、CHK1、RAD51、DNA聚合酶θ(POLQ)、泛素特异性蛋白酶1(ubiquitin-specific protease1, USP1)等，也被开发作为放化疗增敏剂的候选者[2, 50-54]。WEE1、CHK1是调节S、G2/M检查点转换的丝氨酸-苏氨酸激酶，其相关抑制剂可使肿瘤细胞在没有充分修复DNA损伤的情况下通过G2/M检查点，从而影响有丝分裂，最终导致细胞死亡[42, 50]。RAD51是一条由339个氨基酸组成的多肽，它与BRCA2结合会促进HR修复，抑制它可以有效抑制HR修复，从而有效杀伤肿瘤细胞。POLQ是一种独特的家族聚合酶，其在选择性非同源末端连接(alt-NHEJ)或微同源介导的末端连接(MMEJ)修复过程中发挥着重要作用。抑制它可以抑制相关的修复过程从而达到杀伤肿瘤的目的[55]。USP1属于泛素特异性蛋白酶家族的成员，它可以提高BRCA1缺陷型细胞的存活率，其抑制剂有望治疗部分具有BRCA1缺陷型的肿瘤[56]。
三、DDR抑制剂联合放疗、化疗诱导免疫反应DDR抑制剂联合放疗、化疗的过程中可以增强DSBs，然后断裂的DNA片段释放到细胞质中，损伤的DNA可以促发以cGAS-STING通路主导的免疫反应[57-58]。首先细胞质中的DNA片段与cGAS结合进而触发第二信使和免疫递质环鸟苷酸-腺苷酸(cyclic GMP-AMP, cGAMP)的产生[59]。产生的cGAMP可以通过间隙连接扩散到相邻细胞[60]，cGAMP激活位于内质网(endoplasmic reticulum, ER)的STING，然后激活核因子κB(nuclear factor kappa-B, NF-κB)和干扰素调节因子3 (interferon regulatory factor 3, IRF3)转录途径进而诱导促炎性细胞因子、Ⅰ型干扰素(IFN-α和IFN-β)的表达[61](图 1)。最终Ⅰ型干扰素在内的细胞因子的表达会刺激抗原呈递细胞(antigen-presenting cells, APC)并激活T细胞[62]。
在肝细胞癌的研究过程中，Sheng等[63]发现在IR的作用下，ATR抑制剂AZD6738的加入会使CD8+T细胞的浸润和活化进一步增加，并且发现AZD6738成功地逆转了辐射下小鼠异种移植物中调节性T细胞(regulatory cells, Tregs)的免疫抑制作用。Li等[64]发现ATR抑制剂M4344联合拓扑替康会激活STING-IFN反应，并表明此组合可以增强STING低表达的小细胞肺癌的炎症水平。Jo等[65]也表明ATR抑制剂AZD6738联合拓扑替康显著抑制小鼠体内人乳腺癌和结肠癌异种移植物的生长。
四、总结与展望DDR抑制剂联合放疗、化疗已经成为了近年来治疗耐受性肿瘤的常用手段之一，其组合在临床治疗肿瘤过程中表现出了很好的效果。一方面，IR和化疗药物可以诱导DNA损伤，DDR抑制剂可以抑制DNA损伤修复，从而放大肿瘤细胞的DNA损伤。另一方面，由DNA损伤促发的免疫反应可以有效激活机体的抗肿瘤免疫，从而抑制肿瘤转移和复发。此外，IR和某些化疗药物(如蒽环类药物、奥沙利铂等)可以引起免疫原性细胞死亡(immunogenic cell death, ICD)。ICD伴随着大量损伤相关分子模式(DAMPs)的暴露和释放，最终DAMPs(如钙网蛋白、ATP等)可以激活机体的抗肿瘤免疫反应。而通过监测包括DAMPs的相关ICD标志物有助于筛选出合适的ICD诱导剂，开发个性化抗癌方案，并确定癌症临床治疗的最佳治疗组合[66]。
值得注意的是，联合治疗时需特别谨慎，除了关注肿瘤细胞的杀伤效果，其对正常细胞的副作用也是非常重要的。精准靶向肿瘤部位的治疗是一种有前景的治疗方式，纳米技术的发展为此提供了良好的机遇，将具有X射线吸收性能的纳米材料作为联合治疗的载体，精准递送DDR抑制剂到肿瘤部位。纳米粒子可以有效沉积X射线，在达到相同治疗效果的情况下降低辐照剂量，从而减轻对周围正常组织的损伤。Liu等[67]研究发现，超小氧化铪纳米颗粒负载ATR抑制剂berzosertib可以有效增强乳腺癌细胞的放射敏感性，抑制肿瘤生长。Xu等[68]合成的金属纳米颗粒通过间接降解RAD51蛋白来抑制HR修复，以增强肿瘤细胞放射敏感性。同时，纳米粒子还可以将化疗药物和DDR抑制剂精准递送到肿瘤部位，从而避免对正常组织的损伤[69]。总之，纳米粒子联合DDR抑制剂在增强放疗、化疗敏感性的同时，可以减轻对正常细胞的损伤，是具有发展潜力的肿瘤治疗方式，值得进行深入探索。
利益冲突 无
作者贡献声明 何远芳负责文献调研、撰写论文；刘瑞雪负责设计论文框架、论文修订；闫海丽指导论文修改；杜江锋指导写作思路、论文审校
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