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Article(id=1207433495786394486, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1207433493215289544, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.2022.08.0838, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1627228800000, receivedDateStr=2021-07-26, revisedDate=null, revisedDateStr=null, acceptedDate=1630857600000, acceptedDateStr=2021-09-06, onlineDate=1765804178424, onlineDateStr=2025-12-15, pubDate=1661616000000, pubDateStr=2022-08-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1765804178424, onlineIssueDateStr=2025-12-15, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1765804178424, creator=13701087609, updateTime=1765804178424, updator=13701087609, issue=Issue{id=1207433493215289544, tenantId=1146029695717560320, journalId=1189873630562394117, year='2022', volume='47', issue='8', pageStart='745', pageEnd='850', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1765804177811, creator=13701087609, updateTime=1765804292764, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1207433975413444883, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1207433493215289544, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1207433975413444884, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1207433493215289544, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=838, endPage=844, ext={EN=ArticleExt(id=1207433496117744512, articleId=1207433495786394486, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Research advances of targeting DNA damage response in small cell lung cancer, columnId=1190243275882729994, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Review, runingTitle=null, highlight=null, articleAbstract=

Small cell lung cancer (SCLC) is an aggressive malignancy with a 5-year survival rate of 7.2%, which is characterized by exceptionally high proliferation rate, early metastasis, and poor prognosis. In the face of DNA damage and replicative stress, the DNA damage response (DDR) elicits activation of cell cycle checkpoints to promote repair by pausing the cell cycle or, in cases of unrepairable DNA damage, stimulate programmed cell death. SCLC carries a high mutation burden and genomic instability, and almost all SCLC tumors have functional inactivation of both TP53 and RB1, which leads to the form of a dysfunctional G1/S checkpoint and results in an increased reliance on subsequent cell cycle checkpoints (S, G2/M) to ensure genome stability and correct chromosomal segregation. Therefore, under the use of radio-chemotherapy for DNA damaging, promoting the cell cycle progress by inhibiting the cycle checkpoints and increasing DNA damage by inhibiting DNA damage repair can be new strategies for targeted therapies in SCLC. In the present article, we review the advances of targeting DDR and it's pathway inhibitors in SCLC, and provide some thoughts for the targeted treatment strategies of SCLC.

, correspAuthors=Chong Bai, authorNote=null, correspAuthorsNote=
*E-mail:
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小细胞肺癌(SCLC)是高度恶性肿瘤，具有增殖速度快、早期转移及预后差的特点，5年生存率仅7.2%。DNA损伤应答(DDR)是机体在面对DNA损伤及复制应激时，通过激活细胞周期检查点、阻滞细胞周期来促进DNA损伤修复，避免未修复的DNA损伤诱导程序性死亡的过程。SCLC具有突变负荷高、基因组不稳定的特征，普遍存在p53及RB1功能失活，致使细胞周期G1/S检查点缺陷，因而更加依赖后续的S、G2/M检查点进行周期阻滞和DNA损伤修复以确保基因组的稳定性及染色体的正确分离。因此，在基于致DNA损伤的放化疗应用背景下，抑制周期检查点以促进周期进程、增加DNA损伤及抑制DNA损伤修复成为SCLC治疗的新策略。本文就靶向DDR及其通路关键分子(PARP、ATR、CHK1/2、WEE1、ATM、Aurora A)抑制剂在SCLC中的研究进展进行综述，以期为SCLC的治疗策略提供思考。

, correspAuthors=白冲, authorNote=null, correspAuthorsNote=
白冲，E-mail：
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赵松韵，硕士研究生，主要从事肺癌预防及诊治方面的研究

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赵松韵，硕士研究生，主要从事肺癌预防及诊治方面的研究

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赵松韵，硕士研究生，主要从事肺癌预防及诊治方面的研究

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靶向DNA损伤应答在小细胞肺癌中的作用研究进展
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赵松韵 1 , 万志杰 2 , 曹曦元 1 , 杨彦勇 2 , 白冲 1, *
解放军医学杂志 | 综述 2022,47(8): 838-844
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解放军医学杂志 | 综述 2022, 47(8): 838-844
靶向DNA损伤应答在小细胞肺癌中的作用研究进展
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赵松韵1, 万志杰2, 曹曦元1, 杨彦勇2, 白冲1, *
作者信息
  • 1海军军医大学第一附属医院呼吸与危重症医学科，上海 200433
  • 2海军军医大学海军医学系舰船辐射医学防护教研室，上海 200433

    • 赵松韵，硕士研究生，主要从事肺癌预防及诊治方面的研究

通讯作者:

白冲，E-mail：
Research advances of targeting DNA damage response in small cell lung cancer
Song-Yun Zhao1, Zhi-Jie Wan2, Xi-Yuan Cao1, Yan-Yong Yang2, Chong Bai1, *
Affiliations
  • 1Department of Respiratory and Critical Care Medicine, Changhai Hospital, Naval Medical University, Shanghai 200433, China
  • 2Department of Marine Radiation Medicine, Faculty of Naval Medicine, Naval Medical University, Shanghai 200433, China
出版时间: 2022-08-28 doi: 10.11855/j.issn.0577-7402.2022.08.0838
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小细胞肺癌(SCLC)是高度恶性肿瘤，具有增殖速度快、早期转移及预后差的特点，5年生存率仅7.2%。DNA损伤应答(DDR)是机体在面对DNA损伤及复制应激时，通过激活细胞周期检查点、阻滞细胞周期来促进DNA损伤修复，避免未修复的DNA损伤诱导程序性死亡的过程。SCLC具有突变负荷高、基因组不稳定的特征，普遍存在p53及RB1功能失活，致使细胞周期G1/S检查点缺陷，因而更加依赖后续的S、G2/M检查点进行周期阻滞和DNA损伤修复以确保基因组的稳定性及染色体的正确分离。因此，在基于致DNA损伤的放化疗应用背景下，抑制周期检查点以促进周期进程、增加DNA损伤及抑制DNA损伤修复成为SCLC治疗的新策略。本文就靶向DDR及其通路关键分子(PARP、ATR、CHK1/2、WEE1、ATM、Aurora A)抑制剂在SCLC中的研究进展进行综述，以期为SCLC的治疗策略提供思考。

DNA损伤  /  DNA修复  /  小细胞肺癌  /  靶向治疗

Small cell lung cancer (SCLC) is an aggressive malignancy with a 5-year survival rate of 7.2%, which is characterized by exceptionally high proliferation rate, early metastasis, and poor prognosis. In the face of DNA damage and replicative stress, the DNA damage response (DDR) elicits activation of cell cycle checkpoints to promote repair by pausing the cell cycle or, in cases of unrepairable DNA damage, stimulate programmed cell death. SCLC carries a high mutation burden and genomic instability, and almost all SCLC tumors have functional inactivation of both TP53 and RB1, which leads to the form of a dysfunctional G1/S checkpoint and results in an increased reliance on subsequent cell cycle checkpoints (S, G2/M) to ensure genome stability and correct chromosomal segregation. Therefore, under the use of radio-chemotherapy for DNA damaging, promoting the cell cycle progress by inhibiting the cycle checkpoints and increasing DNA damage by inhibiting DNA damage repair can be new strategies for targeted therapies in SCLC. In the present article, we review the advances of targeting DDR and it's pathway inhibitors in SCLC, and provide some thoughts for the targeted treatment strategies of SCLC.

DNA damage  /  DNA repair  /  small cell lung cancer  /  targeted therapy
赵松韵, 万志杰, 曹曦元, 杨彦勇, 白冲. 靶向DNA损伤应答在小细胞肺癌中的作用研究进展. 解放军医学杂志, 2022 , 47 (8) : 838 -844 . DOI: 10.11855/j.issn.0577-7402.2022.08.0838
Song-Yun Zhao, Zhi-Jie Wan, Xi-Yuan Cao, Yan-Yong Yang, Chong Bai. Research advances of targeting DNA damage response in small cell lung cancer[J]. Medical Journal of Chinese People’s Liberation Army, 2022 , 47 (8) : 838 -844 . DOI: 10.11855/j.issn.0577-7402.2022.08.0838
正文
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小细胞肺癌(small cell lung cancer，SCLC)是高度恶性肿瘤，约占所有肺癌的15%，5年生存率仅7.2%[1]。60%~70%的SCLC患者在确诊时已处于广泛期，即病灶超过一侧胸腔，发生远处淋巴结及血行转移[2-3]。SCLC对放化疗比较敏感，标准一线化疗伴或不伴免疫治疗的总缓解率(overall response rate，ORR)为60%~65%[2-3]。然而，大多数患者在数月内迅速复发并产生抵抗，对于铂抵抗患者(复发时间<90 d)，二线治疗的ORR约为10%，中位总生存期(overall survival，OS)仅5.4个月；对于铂敏感患者(复发时间≥90 d)，二线治疗的ORR为20%~30%，中位OS也仅7.7个月[4]。尽管免疫疗法给肿瘤治疗带来了革命性的变化，然而SCLC普遍表现为免疫抑制表型，T淋巴细胞浸润少，约80%的患者程序性死亡配体1(programmed death ligand 1，PD-L1)表达水平低于1%，免疫治疗的效果有限[3]。
DNA损伤应答(DNA damage response，DDR)是机体细胞在遭受内源性或外源性因素干扰造成DNA损伤及复制应激时，产生的涉及损伤识别、修复或清除以维持基因组完整性及恢复细胞稳态的保护性反应。大多数肿瘤在发生发展中存在DDR缺陷，致使驱动基因差错累积，如基因拷贝数的改变、重排及突变等，进而推动肿瘤的克隆进化[5-6]。DDR缺陷及肿瘤细胞快速而不受控分裂的复制压力造成的基因组不稳定，使肿瘤细胞能够对致DNA损伤的干预产生应答，而机体正常细胞则能在一定程度上应对损伤继续存活[6]。也有研究证实，DDR通路抑制剂能够通过增加肿瘤突变负荷、激活STING通路等途径增强抗肿瘤免疫应答[5]。因此，DDR通路抑制剂不仅是研究传统放化疗增敏的热点，还是增强免疫治疗效果的热门方向。本文主要对DDR及其通路关键分子(PARP、ATR、CHK1/2、WEE1、ATM、Aurora A)抑制剂在SCLC中的抗肿瘤机制及其相关临床研究进行综述。
1 SCLC放化疗方案及其作用机制
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SCLC病因不清，吸烟是其重要的致病因素，98%的SCLC患者有吸烟史，吸烟暴露造成DNA损伤累积，并诱导产生高突变负荷；且由于普遍存在p53及RB1的功能失活，SCLC还具有增殖速度快、基因组不稳定的特征[7]。这些特征致使SCLC对致DNA损伤的放化疗较为敏感，并过分依赖完整的DDR以确保基因组稳定性而存活。
目前，SCLC的标准一线化疗方案为铂类(卡铂或顺铂)联合依托泊苷。铂类化疗药物主要通过与DNA链内交联形成加合物，造成DNA损伤[8]。拓扑异构酶Ⅰ及拓扑异构酶Ⅱ主要通过瞬时催化单链、双链DNA断裂来减少DNA超螺旋，从而使DNA解链[9]。拓扑异构酶Ⅰ抑制剂，如伊立替康及拓扑替康，可通过稳定拓扑异构酶Ⅰ/DNA切割复合物而阻碍断裂的DNA单链重新连接，同时，其形成的三元复合物可进一步与DNA复制酶相互作用造成双链DNA损伤；同样，拓扑异构酶Ⅱ抑制剂如依托泊苷可导致断裂的双链DNA不能重新连接[9]。放疗可直接通过次级电子或间接通过活性氧造成严重的DNA双链断裂(double-strand breaks，DSBs)[10]。上述传统放化疗在损伤DNA的同时，也增强了复制应激(DNA复制时遭遇损伤DNA)。当细胞试图复制受损DNA时，复制叉上的聚合酶将暂时停止工作，也称“复制叉停滞”，停滞的复制叉在修复受损DNA后继续复制；抑或经历“复制叉坍塌”，复制酶复合物分离并终止复制，常伴核酸内切酶介导切割形成DSBs[11]。理论上，DDR通路抑制剂与致DNA损伤的放化疗具有协同作用。
2 DDR概述
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在DNA损伤及复制应激时，DDR可通过识别不同的损伤类型激活复杂的信号网络，阻滞细胞周期以促进DNA修复，或通过凋亡、衰老等途径清除未能修复损伤DNA的细胞[12]。DDR通路抑制剂杀伤肿瘤细胞的机制主要是调控细胞周期进程并阻断DNA修复，造成DNA损伤累积并诱发肿瘤细胞的凋亡及衰老。DNA损伤修复的机制主要包括错配修复、碱基切除修复、核酸切除修复、单链断裂修复、双链断裂修复。DSBs主要由需要姐妹染色单体作为模板的同源重组及断端直接连接的非同源末端连接进行修复，此外还有选择性非同源末端连接、单链退火修复。这些机制交互形成复杂的网络，互为补偿。其中单链断裂是最常见的DNA损伤，而DSBs则最为致命。在G1期及S早期，由于不存在姐妹染色单体，DSBs依赖于DNA-PK介导的非同源末端连接修复，这种修复大多时候是正确修复，但也有可能导致小的插入或缺失；在S后期及G2期，DSBs能利用姐妹染色单体作为同源模板进行无差错的同源重组修复[13]。SCLC普遍存在p53及RB1的功能失活，致使细胞周期G1/S检查点缺陷并增加了基因组的不稳定性，因此SCLC更依赖后续的S、G2/M检查点进行周期阻滞及DNA损伤修复，以确保基因组的稳定性及染色体正确分离[7]。在致DNA损伤放化疗的作用下，一些DDR通路中参与调控S、G2/M期的激酶就成为抗肿瘤的重要靶点，如共济失调毛细血管扩张突变Rad3相关激酶(ataxia telangiectasia and Rad3-related，ATR)、细胞周期检查点激酶1(checkpoint kinase 1，CHK1)、WEE1蛋白激酶(WEE1-like protein kinase，WEE1)。此外，SCLC细胞周期进程失控(G1/S检查点失活)及伴随的DNA损伤，使得抑制S期及G2期的DNA损伤修复通路也成为重要的抗癌策略，如参与单链断裂修复的聚腺苷二磷酸核糖聚合酶(poly ADP ribose polymerase，PARP)。相关研究也证实，DDR通路相关分子PARP、ATR、CHK1、WEE1、共济失调毛细血管扩张突变(ataxia telangiectasia-mutated，ATM)在SCLC中高表达[14-15]。
3 DDR通路抑制剂
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3.1 PARP
PARP超家族有17个成员，参与DDR的主要是PARP1、PARP2，二者在结构及功能上相似，其中PARP1承担了约90%的功能[16-17]。PARP1主要参与单链断裂修复，这种损伤可由拓扑异构酶Ⅰ抑制剂等化疗药物、放疗及自由基等直接切割产生，亦可在碱基切除修复过程中间接形成[17]。PARP1与单链断裂位点结合，催化烟酰胺腺嘌呤二核苷酸(NAD+)，分解为烟酰胺及ADP-核糖，进一步使自身及其他细胞核蛋白形成聚ADP-核糖链(也称“PAR化”)[16]。ADP-核糖链招募支架蛋白XRCC1、DNA聚合酶、DNA连接酶3等DNA修复蛋白至损伤位点，并使PAR化的组蛋白及PARP1与DNA链解离，进而继续进行单链断裂修复[16]。2005年，两项研究首次证实了PARP抑制剂与BCRA1/2基因突变之间存在“合成致死”效应[18-19]。最初研究认为，PARP抑制剂致使大量断裂的单链累积，并在DNA复制期(S期)因复制叉坍塌形成DSBs，而BCRA1/2基因突变易造成同源重组修复缺陷，最终DSBs不能被同源重组精确修复，导致基因组不稳定性增加、有丝分裂灾难，进而导致细胞死亡[5, 18]。还有研究进一步发现，PARP抑制剂对癌细胞的杀伤力大于敲除PARP基因本身，这是由于PARP抑制剂与NAD+竞争结合抑制PARP催化活性时，也阻断了PARP与DNA链的解离，此即“诱捕”作用[16-17]。其使得复制叉阻滞并进一步坍塌，最终形成复制相关的DSBs。
当前研究最多的5个PARP抑制剂为尼拉帕尼(Niraparib)、卢卡帕尼(Rucaparib)、他拉唑帕尼(Talazoparib)、奥拉帕尼(Olaparib)、维利帕尼(Veliparib)。从目前发表的研究来看，PARP抑制剂单药总体安全性较好，常见的不良反应主要包括血液系统毒性(白细胞、血小板、中性粒细胞减少)、胃肠道症状及乏力[5]。一项Ⅰ期临床试验结果显示，23例接受他拉唑帕尼1.0 mg/d治疗的SCLC患者中仅有2例获得部分缓解(9%)，持续时间分别为12.0、15.3周；4例疾病稳定，持续至少16周[20]。然而，在针对SCLC的STOMP试验中，采用奥拉帕尼在一线顺铂加依托泊苷方案后维持治疗，其OS及无进展生存期(progression-free survival，PFS)与安慰剂组无明显差异[21]。国内一项针对铂敏感的广泛期SCLC患者在标准一线治疗后采用尼拉帕尼维持治疗的Ⅲ期临床研究显示，其未达到主要终点，仅能够轻微改善患者的PFS，但OS无获益。在该研究中，125例尼拉帕尼组的3级及以上不良反应发生率为34.4%，60例安慰剂组的3级及以上不良反应发生率为25.0%，以血液系统毒性及肝功能损害常见。两组分别有5例(4.0%)和3例(5.0%)患者因不良反应需要停药，显示出尼拉帕尼良好的安全性[22]。鉴于单药效果有限，放疗、化疗联合免疫治疗方案成为探索SCLC治疗的方向。一项替莫唑胺联合奥拉帕尼治疗50例Ⅰ/Ⅱ期复发SCLC患者的单臂研究显示，其ORR为41.7%，中位PFS为4.2个月，中位OS为8.5个月，效果较单药明显[23]。一项Ⅱ期临床研究比较了替莫唑胺联合维利帕尼或安慰剂治疗复发SCLC的疗效及安全性，结果显示两组PFS及OS无明显差异，但进一步对替莫唑胺联合维利帕尼组分析发现，SLFN11(能参与DNA损伤及复制应激反应)阳性表达患者的PFS(5.7个月 vs. 3.6个月，P=0.009)及OS(12.2个月 vs. 7.5个月，P=0.014)显著改善；血液系统毒性仍是两组最常见的不良反应，其中替莫唑胺联合维利帕尼组出现3或4级血小板减少27例(50%)，但仅1例出现咯血症状，经支气管镜检查发现存在支气管内病变[24]。ECOG-ACRIN 2511研究在一线治疗广泛期SCLC中，将患者分为维利帕尼、顺铂、依托泊苷三药联合组与维利帕尼联合安慰剂组，结果显示，三药联合会增加血液系统毒性，但并不影响化疗方案的实施，两组中位PFS分别为6.1个月及5.5个月(未分层HR=0.75，单侧P=0.06；分层HR=0.63，单侧P=0.01)，中位OS分别为8.9个月及10.3个月(分层HR=0.83，单侧P=0.17)。该研究亚组分析表明，维利帕尼联合标准一线化疗方案能明显改善乳酸脱氢酶水平较高、男性广泛期SCLC患者的PFS，这可能是因为该亚组包含了足够比例的、具有某种分子异常的、能够从PARP抑制剂联合化疗中获益的患者[25]。另一项Ⅱ期临床研究表明，维利帕尼联合卡铂及依托泊苷一线并维持治疗广泛期SCLC，患者的PFS仅获得轻微改善，而OS未能获益[26]。
PARP抑制剂能够对SCLC细胞系及人源肿瘤异种移植模型的放疗起到增敏作用[27]。广泛期SCLC联合放疗的早期研究也正在进行中(NCT03532880、NCT04170946)。临床前研究显示，PARP抑制剂可上调SCLC细胞系PD-L1的表达水平，增加CD8+ T细胞浸润，并可激活STING通路，增强SCLC小鼠的抗肿瘤免疫活性[28]。一项纳入20例德瓦鲁单抗(Durvalumab)联合奥拉帕尼治疗后复发SCLC患者的单臂Ⅱ期临床研究(NCT02484404)显示，在可评估的19例患者中，1例部分缓解，1例完全缓解，4例病情稳定。该研究并未达到主要研究终点，其ORR与CheckMate032研究中纳武利尤单抗(Nivolumab)单药治疗复发SCLC的ORR相仿[29]。同时，一项关于卢卡帕尼联合纳武利尤单抗治疗铂类敏感的广泛期SCLC的研究(NCT03958045)正在进行中。目前所进行的单药及联合用药研究结果尚不令人满意，而部分研究进一步行亚组分析发现，一些分子特征(如SLFN11)与疗效密切相关，考虑相关研究普遍未对SCLC患者进行分子筛选，因而明确有效的生物预测标志物显得十分必要。
3.2 ATR
ATR由大范围的基因毒性应激激活，参与多种类型DNA损伤的修复。ATR是复制应激的主要调节因子，当遭受细胞内外因素的复制应激时，DNA复制叉停滞，MCM解螺旋酶在复制叉下游解开几百个碱基对，致使单链DNA累积[11]。ATR通过其伴侣蛋白ATRIP被募集至覆盖有磷酸化复制蛋白A的单链DNA，并通过TopBP1或ETAA1激活ATR激酶，活化的ATR可以磷酸化下游CHK1以参与DDR[30-31]。此外，ATR/CHK1激活导致WEE1激活及CDC25A失活，CDC25A失活能通过降低细胞周期依赖激酶活性而减慢或阻滞细胞周期进程，为DNA修复提供时间[30-31]。ATR/CHK1/WEE1通路的激活有效代偿了DNA复制应激，使S期复制叉得以稳定并重新开始复制[11]。抑制ATR可导致DNA损伤累积及有丝分裂灾难，最终导致肿瘤细胞死亡。目前有4种ATR抑制剂正在进行临床试验，分别是M6620(VX 970或Berzosertib)、M4344(VX 803)、AZD6738及BAY1895344(ART0380)。一项Ⅱ期临床研究显示，Berzosertib联合拓扑替康方案对复发SCLC的疗效较好，ORR为36%，其中21例难治复发患者(复发时间<90 d)的ORR达30%。在该项研究中，常见的3或4级不良反应为淋巴细胞减少(69.2%)、血小板减少(57.7%)、贫血(53.8%)、中性粒细胞减少(15.4%)，无治疗相关的死亡。针对治疗前的样本进行全外显子组及转录组测序发现，ATR激活上调的基因及DDR相关基因在应答者中的表达水平明显高于无应答者[32]。此外，也有几项ATR抑制剂联合不同化疗及免疫治疗SCLC的研究正在进行，如Berzosertib联合拓扑替康治疗复发铂抵抗(复发时间<90 d)SCLC的Ⅱ期临床研究(NCT04768296)，评估Berzosertib联合鲁比卡丁(Lurbinectedin)治疗SCLC的Ⅰ/Ⅱ期临床研究(NCT04802174)，比较Berzosertib联合拓扑替康与拓扑替康单药治疗SCLC的Ⅱ期临床研究(NCT03896503)，AZD6738联合奥拉帕尼治疗复发SCLC的Ⅱ期临床研究(NCT03428607)，AZD6738联合德瓦鲁单抗治疗复发SCLC的Ⅱ期临床研究(NCT04361825)，以及BAY1895344联合其他药物治疗SCLC等固体肿瘤的Ⅰ期临床研究(NCT04491942、NCT04514497)。
3.3 CHK1/2
CHK1及CHK2分别是ATR及ATM的下游靶点，能够抑制细胞周期蛋白依赖性激酶1及2(CDK1/2)，致使G2/M、G1/S期检查点激活以减慢或阻滞细胞周期进程，为DNA损伤提供修复时间。应用CHK1/2抑制剂可致DNA损伤累积并诱发肿瘤细胞的衰老及凋亡。CHK1/2抑制剂临床研究较久，但一代抑制剂因选择性差、脱靶导致不良反应大而终止了临床试验，如UCN 01、AZD7762、Rabusertib。Sen等[15]发现，与非小细胞肺癌(NSCLC)细胞系相比，SCLC细胞系具有更高的CHK1/2蛋白表达水平，二代CHK1/2抑制剂Prexasertib(LY2606368)在SCLC细胞系及小鼠模型中具有良好的抗肿瘤活性。还有研究证实CHK1抑制剂SRA737能增强SCLC的免疫治疗效果[33]。Doerr等[34]开展的临床前研究也证实，靶向ATR/CHK1轴在体外及体内模型中均具有抗SCLC活性。Hsu等[35]开展的临床前研究证实，CHK1抑制剂在治疗SCLC中与顺铂具有协同作用。一项关于单药Prexasertib治疗复发SCLC的Ⅱ期临床研究将无生物预测标志物筛选的118例患者分为铂敏感组(复发时间≥90 d，58例)与铂抵抗组(复发时间<90 d，60例)，铂敏感组中有3例达到部分缓解(ORR为5.2%)，而铂抵抗组的ORR为0；铂敏感组与铂抵抗组常见的不良反应为中性粒细胞减少(69.6% vs. 73.7%)、血小板减少(51.8% vs. 50.0%)、白细胞减少(28.6% vs. 40%)、贫血(39.3% vs. 28.3%)；该研究118例患者中因不良反应需要减少药物剂量者31例(26.3%)，需要停药2例(1.7%)[36]。尽管具有令人信服的临床前研究结果及理论基础，但该研究并未取得预期结果，原因可能是多样的，如服药时间未能达到损伤DNA所需的时间及肿瘤异质性(具有不同分子特征的亚克隆群体)等。一项包含SCLC扩大队列的Ⅰ/Ⅱ期临床试验正在进行(NCT02797977)，该研究旨在探讨CHK1抑制剂SRA737联合化疗在晚期固体肿瘤中的效果，期待其结果能为CHK1抑制剂的应用进一步提供依据。此外，通过联合致DNA损伤的传统放化疗、DDR抑制或免疫治疗以发挥协同作用也是值得探讨的抗肿瘤策略。
3.4 WEE1
WEE1是一种蛋白激酶，其在SCLC组织及细胞系中的表达水平高于正常肺组织和NSCLC组织及细胞系[37]。WEE1也能抑制CDK1/2，从而激活G2/M细胞周期检查点，在DNA损伤时阻止细胞进入有丝分裂，可为DNA损伤修复提供时间[5]。SCLC普遍存在G1/S检查点失活，因此更加依赖后续的G2/M检查点进行DNA损伤修复[7]。临床前研究证实，WEE1抑制剂在SCLC细胞系中具有抗肿瘤活性，对致DNA损伤的放化疗具有增敏作用[5, 37-38]。目前进入临床研究的WEE1抑制剂有Adavosertib(AZD1775、MK-1775)及IMP7068，针对Adavosertib的Ⅱ期临床研究已经证实其在具有TP53(编码p53蛋白)突变、基因组不稳定的复发卵巢癌中的抗肿瘤活性较好，并能改善患者的OS及FPS；进一步行基因分析发现，存在同源重组缺陷及细胞周期蛋白E1(cyclin E1，CCNE1)扩增的患者获益更大[39]。这提示存在TP53突变、基因组不稳定的SCLC患者可能获益于WEE1抑制剂。一项将Adavosertib应用于复发SCLC的Ⅱ期临床试验正在进行(NCT02593019)，其余则主要是关于晚期实体肿瘤的研究。
3.5 ATM
ATM主要参与DSBs的损伤应答，调控同源重组修复、检查点激活、凋亡、衰老、染色质结构、转录及mRNA前体剪接的改变等一系列过程。在S/G2/M期，DSBs端形成的MRE11-RAD50-NBS1(MRN)复合物能够募集并激活ATM，激活的ATM可以磷酸化CtIP，再与BRCA1相互作用，形成BRCA1/MRN/CtIP复合体，促进DNA末端切除形成延伸的单链DNA[30-31]。由于单链DNA相较于双链DNA极不稳定，可迅速被复制蛋白A覆盖，在Rad52或BRCA2的介导下，Rad51替换复制蛋白A，单链DNA的复合物将在双链DNA中寻找同源序列进行同源重组修复。在G1期，ATM-MRN复合物可通过募集53BP1以拮抗同源重组，促进非同源末端连接[30-31]。此外，ATM还能激活CHK2，CHK2及ATM均可激活p53，进而导致细胞发生G1/S期阻滞、衰老及凋亡[5, 30]。大多数ATM的底物也可被ATR磷酸化以响应复制应激，少数ATM底物如组蛋白H2AX也能被DNA-PKcs磷酸化[30, 32]。
与PARP、ATR、WEE1等其他DDR通路抑制剂相比，ATM抑制剂尚处于研究的早期阶段[40]。目前有4种ATM抑制剂正在进行Ⅰ期临床研究，分别是M4076在晚期固体肿瘤中的单药研究(NCT04882917)，M3541联合姑息放疗在固体肿瘤中的研究(NCT03225105)，AZD0156单药及联合其他化疗方案在晚期固体肿瘤中的研究(NCT02588105)，以及AZD1390联合放疗治疗头颅肿瘤的研究(NCT03423628)。鉴于ATM与ATR联系密切，尤其在参与双链断裂修复中具有关键作用，期待进一步看到ATM在SCLC治疗中的探索应用。
3.6 Aurora激酶A
Aurora激酶A(Aurora kinase A，Aurora A)为丝氨酸/苏氨酸激酶，在有丝分裂及胞质分裂中发挥重要作用，参与中心体成熟及纺锤体组装；此外，Aurora A还参与G2/M期转换，调控细胞周期进程[41]。最近研究发现，Aurora A及TPX2可参与DSBs的修复，通过负向调节53BP1功能促进DSBs的DNA末端切除及同源重组，并使复制应激时停滞的复制叉中间体免受MRE11的广泛降解以维持复制叉稳定[42]。Aurora A在SCLC中呈过表达，体外实验证实，敲低Aurora A基因可抑制SCLC增殖[43]。Myc扩增在SCLC中约占20%，细胞及动物模型实验进一步证实，SCLC中Myc扩增联合Aurora A抑制剂具有协同作用[44]。
Alisertib是高效的Aurora A选择性抑制剂。一项采用单药Alisertib治疗48例复发SCLC的Ⅱ期临床试验结果显示，ORR为21%，中位PFS为2.1个月[45]。该研究中，药物相关的3或4级不良反应发生率为53%，以中性粒细胞减少为主(37%)。在另一项比较紫杉醇联合Alisertib与紫杉醇联合安慰剂的Ⅱ期临床试验中，每组均纳入89例复发SCLC患者，结果显示，紫杉醇联合Alisertib组的中位PFS为3.32个月，紫杉醇联合安慰剂组为2.17个月，差异无统计学意义(P=0.113)；紫杉醇联合Alisertib组的中位OS为6.86个月，紫杉醇联合安慰剂组为5.58个月，差异无统计学意义(P=0.714)。虽然统计分析无明显差异，但对复发类型进行分层分析发现，在铂抵抗患者中，紫杉醇联合Alisertib组的中位PFS为2.86个月，长于紫杉醇联合安慰剂组(1.68个月)，差异有统计学意义(P=0.037)，但未观察到生存获益。进一步进行基因分析发现，细胞周期调节因子突变(CDK6、RBL1/2、RB1)显著改善了紫杉醇联合Alisertib组的中位PFS及OS，紫杉醇联合Alisertib组中位PFS为3.68个月，中位OS为7.20个月，大于紫杉醇联合安慰剂组(1.80、4.47个月)，差异有统计学意义(P<0.001)。此外，该研究还选取了46例SCLC组织样本进行c-Myc免疫组化分析，33例(72%)阳性、13例(28%)阴性，在c-Myc阳性患者中，紫杉醇联合Alisertib组的中位PSF为4.64个月，大于紫杉醇联合安慰剂组的2.27个月，提示c-Myc表达及细胞周期调节因子突变可能是Alisertib的潜在预测性生物标志物，但仍需要前瞻性研究进行验证。紫杉醇联合Alisertib组的3或4级不良反应发生率为67%，大于紫杉醇联合安慰剂组的22%[46]。目前尚未见到Aurora A联合免疫治疗SCLC的临床研究，这是今后值得研究的重要方向。
4 总结与展望
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目前，SCLC的治疗手段有限，临床前研究显示DDR通路抑制剂在SCLC细胞系及动物模型中具有良好的抗肿瘤效果，但目前的临床试验设计普遍没有基于临床前研究进行患者筛选，单纯联合放化疗并不总是基于良好的DDR机制及生物学基础。今后仍需进一步明确DDR抑制剂的生物预测标志物，以及联合给药的剂量、顺序，只有致DNA损伤的措施以适当剂量及时间干预肿瘤后，DDR抑制剂才能发挥更好的作用。鉴于大量临床前研究已证实DDR通路抑制剂能增强SCLC的免疫应答，联合免疫治疗也是未来DDR抑制剂应用的方向。
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2022年第47卷第8期
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doi: 10.11855/j.issn.0577-7402.2022.08.0838
  • 接收时间：2021-07-26
  • 首发时间：2025-12-15
  • 出版时间：2022-08-28
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  • 收稿日期：2021-07-26
  • 录用日期：2021-09-06
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    1海军军医大学第一附属医院呼吸与危重症医学科，上海 200433
    2海军军医大学海军医学系舰船辐射医学防护教研室，上海 200433

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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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