Molecular mechanisms and treatment strategies for recurrence of isocitrate dehydrogenase mutation glioma
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摘要: 异柠檬酸脱氢酶突变(mIDH)在神经胶质瘤的治疗与预后评估中扮演着重要角色。与野生型相比，mIDH胶质瘤患者具有较好预后前景，但也伴随着治疗抵抗和疾病复发的挑战，其复发机制涉及基因组不稳定、亚型转换、干细胞更新、新陈代谢模式改变以及免疫微环境动态调整等多个方面。深入了解mIDH胶质瘤复发抵抗机制对于制定和优化治疗策略至关重要，包括合成致死、放化疗增敏、靶免联合等治疗策略。本文综述了mIDH胶质瘤的复发机制及相应的应对策略，为相关研究提供新的视角与思路。Abstract: Isocitrate dehydrogenase mutation(m IDH) influences the treatment and prognosis of glioma. Compared with the wild type, the glioma patients with m IDH have better prognosis, but they are also accompanied by challenges of treatment resistance and disease recurrence. The recurrence mechanism involves multiple aspects such as genomic instability, subtype transformation, stem cell renewal, changes in metabolic patterns, and dynamic adjustments of the immune microenvironment. An in-depth understanding of the recurrence resistance mechanism of glioma with m IDH is crucial for formulating and optimizing treatment strategies, such as synthetic lethal, chemoradiotherapy sensitization, and combination of targeted therapy and immunotherapy. This article reviews the recurrence mechanism of m IDH glioma and the corresponding coping strategies, so as to provide new perspectives and ideas for related research.
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异柠檬酸脱氢酶突变（isocitrate dehydrogenase mutation，mIDH）在多种肿瘤中广泛存在，包括急性髓系白血病、胶质瘤、软骨肉瘤与肝内胆管细胞癌等，是一个重要的分子标志物[1-2]。异柠檬酸脱氢酶（isocitrate dehydrogenase，IDH）有IDH1、IDH2和IDH3 3种亚型，常见的热点突变有IDH1 R132C/H/S/L和IDH2 R140Q、R172V/K等，mIDH3目前尚未见报道[3]。正常情况下，IDH催化三羧酸循环中异柠檬酸转化为α-酮戊二酸（α-ketoglutarate，α-KG）过程，但突变的IDH可以将α-KG转化为2-羟基戊二酸（2-hydroxyglutaric acid，2-HG）[4]。由于与α-KG结构相似，2-HG会竞争性结合一系列依赖α-KG的加氧酶，导致基因组与蛋白质组的甲基化异常、染色质结构重塑及细胞分化阻滞等表观遗传变化。目前，针对mIDH的治疗策略主要通过使用mIDH抑制剂来阻断这一异常代谢途径（表 1）。mIDH胶质瘤Ⅰ期临床试验（NCT03343197）中AG881与AG120分别取得42.9%和35.7%的客观缓解率；其Ⅲ期关键性研究（NCT04164901）进一步证实，AG881治疗组较安慰剂组延长了中位无进展生存期（27.7个月vs 11.1个月，P＜0.001）[5]，AG881已被美国FDA批准用于治疗mIDH胶质瘤[6-7]。
表 1 美国FDA已批准的异柠檬酸脱氢酶突变抑制剂抑制剂类型 药品名称 临床适应证 获批时间 异柠檬酸脱氢酶1突变抑制剂 艾伏尼布(AG120) 复发或难治性急性髓系白血病a 2018-07-20 新诊断的急性髓系白血病 2019-05-02 局部晚期或转移性胆管癌 2021-08-25 骨髓增生异常综合征 2023-10-24 奥鲁西尼布(FT2102) 2023-10-24 复发或难治性急性髓系白血病 2022-12-01 异柠檬酸脱氢酶2抑制剂 恩西尼布(AG221) 复发或难治性急性髓系白血病 2017-08-01 异柠檬酸脱氢酶1/2抑制剂 沃拉西尼布(AG881) 2级星形胶质细胞瘤或少突胶质细胞瘤 2024-08-06 a：中国已批准的适应证. FDA：食品药品监督管理局. 目前mIDH抑制剂尚未被纳入胶质瘤的标准一线治疗方案，临床实践以手术切除联合放化疗作为首选治疗手段，患者治疗后会面临较高的肿瘤复发风险。脑神经胶质瘤的空间异质性、克隆进化分支差异、手术和放疗难以彻底清除浸润性病灶、免疫微环境重塑等因素共同促进了肿瘤的复发。本文对近年来mIDH胶质瘤在标准治疗后复发可能涉及的多种分子机制（图 1）及其治疗策略进行综述，旨在为mIDH胶质瘤的临床治疗提供有价值的参考。
图 1 IDH突变胶质瘤复发机制概略图IDH：异柠檬酸脱氢酶；CDKN2A/B：细胞周期蛋白依赖性激酶抑制因子2A/B；NAD+：烟酰胺腺嘌呤二核苷酸；Bcl-2：B淋巴细胞瘤基因2；NK细胞：自然杀伤细胞；2-HG：2-羟基戊二酸；PI3K：磷脂酰肌醇3激酶；Akt：蛋白激酶B；MAPK：丝裂原活化蛋白激酶；mTOR：哺乳动物雷帕霉素靶蛋白；STAT3：信号转导及转录活化因子3；ASPN：无孢蛋白；TGFβ1：转化生长因子β1；GPM6A：糖蛋白M6A.
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1 mIDH胶质瘤复发机制
1.1 DNA水平的不稳定
mIDH引起2-HG异常积累并竞争性结合一系列依赖α-KG的加氧酶，从而抑制了多种类型双加氧酶的活性。如2-HG抑制10-11易位蛋白家族酶活性，导致DNA甲基化受阻，进而引起甲基化异常[8-9]。此外2-HG还可以抑制α-KG依赖的双加氧酶同源物DNA修复酶活性[10]，影响DNA损伤修复能力，从而导致个别碱基突变或多个基因的超突变[11]。
1.1.1 DNA甲基化异常
在mIDH胶质瘤中，2-HG引起的DNA甲基化水平变化被认为是肿瘤发生、发展和复发的重要因素[12]。临床突变与野生型复发样本表观基因组显示，mIDH胶质瘤复发后DNA甲基化丢失比例高于野生型胶质瘤患者[39%（28/72）vs 8%（5/60），P＝0.000 6][13]。类似的，有病例报告报道了1例原发性mIDH胶质瘤复发的甲基化位点发生显著变化，特别是O6-甲基鸟嘌呤-DNA甲基转移酶（O6-methylguanine DNA methyltranferase，MGMT）启动子甲基化区域的丢失[12]。在mIDH伴随H3 K27M突变弥漫性中线胶质瘤中，MGMT的表达能增强对替莫唑胺（temozolomide，TMZ）的耐药性，而MGMT沉默能增加mIDH胶质瘤对TMZ的敏感性[13-14]。因此，在mIDH胶质瘤治疗反应中，MGMT启动子甲基化状态可用于评估胶质瘤患者对TMZ治疗的反应性，有助于临床制定个体化治疗策略。
1.1.2 IDH亚型转换
mIDH急性髓系白血病复发机制包括IDH1和IDH2两种亚型相互转换与叠加，以及外显子区碱基突变引起的氨基酸替换[15]。mIDH胶质瘤存在类似的机制，导致从相对惰性的mIDH胶质瘤向侵袭性较强的IDH野生型胶质母细胞瘤转变，有研究报道了6例IDH1 R132H突变星形胶质细胞瘤复发后转变为IDH野生型胶质母细胞瘤的病例[16-17]。还有研究报道了1例复发后中央前病灶活检存在2种不同亚型mIDH1（幕下病灶为IDH1 R132G突变，皮质病灶为R132H突变）的病例[18-19]。这表明mIDH胶质瘤的细胞表型和遗传特征在肿瘤进化过程中可能发生动态转变[17, 20]。
1.1.3 基因超突变
mIDH胶质瘤中，超突变通常与肿瘤细胞的增殖能力增强相关，因此被认为是肿瘤进展的重要推动因素[21]。在mIDH胶质瘤中，DNA烷基化剂TMZ能诱导更多的DNA损伤和肿瘤细胞凋亡[10, 22]，正常情况下TMZ治疗导致的错配会通过错配修复机制被细胞自身识别并修复，从而避免基因突变。错配修复机制失活会导致大量突变基因积累，形成超突变表型，当患者存在大量超突变基因时可能会出现治疗抵抗，进而导致肿瘤复发[23-24]。尤其是在原发性错配修复缺陷型mIDH星形胶质细胞瘤和mIDH低级别胶质瘤中，容易产生化疗驱动的超突变[25]，并伴随肿瘤突变高负荷和微卫星不稳定等现象[26]。其中，微卫星不稳定是一种复发性mIDH神经胶质瘤对烷基化剂耐药的机制[26]。
1.2 染色体周期蛋白依赖性激酶抑制因子2A（cyclin-dependent kinase inhibitor 2A，CDKN2A）与1p/19q缺失状态
mIDH胶质瘤携带1p/19q共缺失（codel）的患者更适用于中国抗癌协会胶质瘤诊疗指南推荐的标准化治疗方案[27]；而携带CDKN2A缺失的患者由于肿瘤较强的侵袭性往往需要采取强化治疗策略，例如对侵袭性较强的IDH野生型胶质瘤放射治疗时增加射线剂量[28-29]。研究表明，相较于mIDH伴1p/19q共缺失的胶质瘤患者，不伴1p/19q共缺失者有更高的复发风险[30]，且复发后的mIDH胶质瘤会失去1p/19q部分缺失并对TMZ产生耐药性[31-32]。
1.3 线粒体代谢异常
mIDH引起的2-HG积累导致细胞代谢重编程，从而影响线粒体的功能和代谢途径。其中，高度的代谢应激和细胞内的烟酰胺腺嘌呤二核苷酸（nicotinamide adenine dinucleotide，NAD+）水平降低会影响细胞的能量代谢和生存能力[22, 33-35]，导致部分肿瘤细胞在化疗或放疗后仍能够利用突变重塑细胞代谢、维持细胞存活并最终导致肿瘤复发。例如，依赖于线粒体功能的凋亡诱导剂依托泊苷在mIDH胶质瘤细胞中敏感性降低[36]。另外2-HG诱导Bcl-2在线粒体膜积聚，使高琥珀酰化细胞对凋亡产生抵抗[37]。lncRNA HOXA反义转录物髓系异构体1与线粒体卷曲螺旋结构域蛋白2可以介导胶质母细胞瘤细胞缺氧诱导的侵袭和治疗抵抗[38-39]。线粒体离子肽酶1在IDH R132H突变胶质瘤中通过核因子-红细胞2相关因子2和神经前间充质转化途径响应肿瘤微环境中的应激信号，增强前膜-间质转化，促进肿瘤进展[40]。由此可见，mIDH会通过改变线粒体的代谢模式诱导肿瘤复发。
1.4 干细胞更新
肿瘤干细胞的特殊性是肿瘤恶性生长和复发的部分原因。肿瘤干细胞具有较强的自我更新能力和分化潜力，在原发肿瘤大块生长之前往往已经微浸润了整个脑实质，从而易导致后期的复发[21]。一项空间组学研究显示，复发性mIDH胶质瘤表现出高水平的增殖样肿瘤干细胞和低水平的分化样肿瘤细胞表型[21]。细胞周期调控因子CDKN2A的缺失与细胞周期蛋白D2的扩增共同促进了干细胞样细胞的异常增殖，与匹配的原发肿瘤相比，复发肿瘤中相关干性基因性别决定区Y框蛋白2/Ki67阳性的细胞数量显著增加[21, 41]。将临床试验复发病例与数据库转录组学数据进行联合分析，结果显示，Notch1突变会抑制mIDH1/2抑制剂AG881的促干性分化[42]。
1.5 免疫逃逸
mIDH胶质瘤的肿瘤微环境通常是免疫抑制性的，其形成机制涉及mIDH驱动的表观遗传重编程和肿瘤源性细胞因子分泌失衡，这构成了肿瘤复发的高风险基础[43]。多项数据库的临床测序数据显示，T细胞表面抑制性免疫检查点T细胞免疫球蛋白黏蛋白结构域3（T cell immunoglobulin and mucin-domain containing 3，TIM-3）低表达导致TIM-3+ T细胞与小胶质细胞/巨噬细胞表面配体半乳糖凝集素-9的相互作用减少，从而促进了免疫逃逸[44-45]；多功能调控因子精脒/精胺N1-乙酰基转移酶1（spermidine/spermine N1-acetyltransferase 1，SAT1）可通过与巨噬细胞、CD8+ T细胞等免疫成分的动态相互作用导致免疫耐受，以及通过抑制自然杀伤细胞族2成员D配体UL16结合蛋白1和3的表达而获得对自然杀伤细胞的抗性[45-46]。体外动物实验研究发现，在mIDH肝内胆管细胞癌小鼠模型中，2-HG抑制CD8+ T细胞募集及干扰素γ表达，并促进肿瘤细胞中干扰素γ反应基因10-11易位蛋白2介导的免疫耐受表型，导致程序性死亡蛋白1治疗反应率下降[47-48]。以上研究提示，这种免疫逃逸模式在肝内胆管细胞癌中也呈现出了跨瘤种保守性。因此，mIDH胶质瘤的免疫原性多样性促进了肿瘤的耐药与复发[49]。
1.6 致癌细胞信号通路的激活
在mIDH胶质瘤中，致癌信号通路的异常是促进肿瘤复发的原因之一。有研究表明，mIDH通过调控PI3K/Akt和MAPK信号通路的活性使肿瘤细胞在面对治疗时更具抵抗力，从而导致肿瘤复发[34]。其中，2-HG介导的哺乳动物雷帕霉素靶蛋白/STAT3信号通路抑制可重塑血管微环境，降低肿瘤血管密度、阻断代谢物质转运及循环细胞外渗，从而形成促复发的低氧生态位[50]。mIDH低级别胶质瘤和IDH野生型高级别胶质瘤的相关血管细胞在转录组层面存在差异，如可通过调节无孢蛋白（asporin）/TGFβ1/糖蛋白M6A信号转导途径干扰肿瘤的生长和复发[51]。此外，SAT1、低氧诱导因子1α和β-连环蛋白等信号通路激活均与放化疗耐药及疾病复发呈正相关[42, 46]。
2 复发性mIDH胶质瘤的治疗策略
对于能够安全切除的复发性mIDH胶质瘤，再次手术与放疗仍然是首选治疗方式。对于复发性IDH野生型胶质瘤进行术中放疗可以很大程度上减小肿瘤体积[52]，这为复发性mIDH胶质瘤治疗提供了一定参考。此外，可以基于2-HG对肿瘤细胞代谢途径的影响，结合多种药物的作用机制，探索联合药物治疗、发掘新型合成致死靶点等策略，以进一步增强治疗效果。
2.1 放疗联合药物治疗
mIDH虽然为放疗提供了有利的预后条件，但仍旧存在部分放射抵抗情况[53]。体外研究发现，联合药物疗法可增强细胞与动物模型对放疗的敏感性。相比单独使用PARP抑制剂，聚腺苷二磷酸核糖聚合酶（poly ADP-ribose polymerase，PARP）抑制剂奥拉帕尼联合放射治疗对mIDH胶质瘤和胆管细胞癌患者的总生存期都有一定的益处[54]。线粒体柠檬酸转运蛋白抑制剂联合放射治疗可以减缓绒毛膜尿囊膜模型体内胶质瘤的生长[55]。没食子儿茶素-3-没食子酸酯和HOXA反义转录物髓系异构体1基因敲除均可抑制谷氨酸的代谢途径，促进放疗时细胞的氧化应激和代谢应激状态，从而提升癌细胞对放疗的敏感性[3, 38, 56]。另外，对于弥漫性TIM-3+胶质瘤细胞，TIM-3抑制剂MBG453与程序性死亡蛋白1抑制剂和立体定向放射治疗联合使用也展现了潜在的治疗优势[44]。
2.2 化疗联合烟酰胺腺嘌呤二核苷酸磷酸（nicotinamide adenine dinucleotide phosphate，NADP）抑制剂治疗
mIDH会损害胶质瘤细胞的线粒体功能，在化疗触发的DNA损伤修复过程尤其是碱基切除修复环节，PARP的激活伴随着NADP/还原型NADP平衡的破坏和对谷胱甘肽代谢的需求增加[57-58]。研究发现，在mIDH1肿瘤患者来源异种移植模型和体外细胞系中，将烟酰胺磷酸核糖基转移酶（nicotinamide phosphoribosyl transferase，NAMPT）抑制剂与TMZ联合应用可以阻断NAD+的生物合成，从而抑制肿瘤生长[57]。选择性NAD+生物合成抑制剂KPT-9274与TMZ联合使用也能够加剧由NAD+耗竭而引起的细胞毒性[33]，并且这一效应可通过外源性补充NAD+逆转，这一结果验证了该策略的特异性[59]。然而，并非所有的NAMPT抑制剂都有协同抑制胶质瘤生长的作用，例如体外实验结果显示NAMPT抑制剂FK866、GMX1778和GNE-617对mIDH1胶质瘤细胞无协同毒性效应，这表明选择NAMPT抑制剂时需要根据患者个体特征考量[60]。
2.3 IDH抑制剂联合免疫治疗
与野生型肿瘤相比，mIDH肿瘤具有独特的免疫表型。例如，mIDH可通过表观遗传调控引起T细胞C-X-C基序趋化因子配体10表达下调，同时伴随T细胞受体信号通路相关基因的转录抑制，导致肿瘤微环境中淋巴细胞浸润减少，进而引起免疫逃逸[61]。研究发现，IDH1 R132H抑制剂BAY1436032与程序性死亡蛋白1抑制剂联合使用可提高mIDH1胶质瘤C57BL/6J小鼠的总生存率[62]。全球首项评估艾伏尼布联合程序性死亡蛋白1抑制剂纳武利尤单抗治疗mIDH1实体瘤的Ⅱ期临床研究（NCT04056910）已于2025年2月27日完成，旨在评估该联合疗法在晚期不可切除/转移性实体瘤及高级别神经胶质瘤患者中的安全性[63]。
2.4 其他天然药物
抗氧化反应元件核因子-红细胞2相关因子2是调控基因表达的关键转录因子，通过遗传干扰手段或药物阻断核因子-红细胞2相关因子2的激活不仅能够打破细胞活性氧稳态，还能加剧DNA损伤，抑制mIDH1细胞的增殖。雷公藤内酯[64]和鸦胆子苦醇[35]作为有效的核因子-红细胞2相关因子2抑制剂，已被证实能抑制患者来源的mIDH1胶质瘤生长[35, 64]。黄吡啶醇对IDH野生型和突变型胶质瘤细胞均有抑制作用，其通过靶向叉头框蛋白M1致癌信号转导通路抑制肿瘤细胞的增殖、存活和迁移，并诱导细胞凋亡[65]。
3 小结
mIDH胶质瘤复发机制包括化疗引起DNA超突变的形成，1p/19q共缺失导致的染色体结构异常，2-HG介导的线粒体代谢增强诱导代谢重编程、抑制肿瘤微环境的免疫原性与促进免疫逃逸，以及肿瘤生长早期即已浸润的肿瘤干细胞等。针对胶质瘤复发机制的治疗方案及联合治疗策略值得进一步探索：一方面，可以利用mIDH带来的损伤脆弱性放大合成致死效应，如采用放化疗联合靶向抑制剂、PARP抑制剂奥拉帕尼或NAD+抑制剂KPT-9274等；另一方面，也可以探索mIDH抑制剂联合免疫抑制剂程序性死亡蛋白1或化疗药物等治疗方案。
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图 1 IDH突变胶质瘤复发机制概略图
IDH：异柠檬酸脱氢酶；CDKN2A/B：细胞周期蛋白依赖性激酶抑制因子2A/B；NAD+：烟酰胺腺嘌呤二核苷酸；Bcl-2：B淋巴细胞瘤基因2；NK细胞：自然杀伤细胞；2-HG：2-羟基戊二酸；PI3K：磷脂酰肌醇3激酶；Akt：蛋白激酶B；MAPK：丝裂原活化蛋白激酶；mTOR：哺乳动物雷帕霉素靶蛋白；STAT3：信号转导及转录活化因子3；ASPN：无孢蛋白；TGFβ1：转化生长因子β1；GPM6A：糖蛋白M6A.
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表 1 美国FDA已批准的异柠檬酸脱氢酶突变抑制剂
抑制剂类型 药品名称 临床适应证 获批时间 异柠檬酸脱氢酶1突变抑制剂 艾伏尼布(AG120) 复发或难治性急性髓系白血病a 2018-07-20 新诊断的急性髓系白血病 2019-05-02 局部晚期或转移性胆管癌 2021-08-25 骨髓增生异常综合征 2023-10-24 奥鲁西尼布(FT2102) 2023-10-24 复发或难治性急性髓系白血病 2022-12-01 异柠檬酸脱氢酶2抑制剂 恩西尼布(AG221) 复发或难治性急性髓系白血病 2017-08-01 异柠檬酸脱氢酶1/2抑制剂 沃拉西尼布(AG881) 2级星形胶质细胞瘤或少突胶质细胞瘤 2024-08-06 a：中国已批准的适应证. FDA：食品药品监督管理局. -
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