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Application of Cyclin-dependent Kinase 4/6 Inhibitors in the Treatment of Malignancies and the Mechanism of Drug Resistance
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摘要: 增殖失控是恶性肿瘤的重要特征之一。细胞周期依赖性激酶4/6(cyclin-dependent kinase 4/6, CDK4/6)抑制剂能作用于各种原因导致的过度活化的CDK4/6，恢复正常细胞周期，并可通过增强免疫、改变肿瘤微环境等发挥抗肿瘤作用。目前，CDK4/6抑制剂在激素受体阳性乳腺癌治疗中取得了良好疗效，已被批准联合内分泌治疗作为此类肿瘤的一线治疗方案，在其他肿瘤中的应用亦逐渐开展，疗效有待验证。对CDK4/6抑制剂天然或获得性耐药是影响其疗效的重要因素，目前激素受体阳性(主要为雌激素受体阳性)能较为准确预测内分泌联合CDK4/6抑制剂治疗的反应性，其他标志物需进一步探索和验证。本文对CDK4/6抑制剂治疗恶性肿瘤的作用机制、应用现状及耐药机制进行梳理和总结，并对当前CDK4/6抑制剂治疗乳腺癌尚存争议的临床决策问题作简要讨论。
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关键词:
- 细胞周期依赖性激酶4/6抑制剂 /
- 细胞周期调控 /
- 乳腺癌 /
- 治疗 /
- 耐药机制
Abstract: Uncontrolled cell proliferation is one of the important hallmarks of malignancies. Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors act on CDK4/6 that is over activated by various causes. CDK4/6 inhibitors play anti-tumor roles by restoring normal cell cycle, enhancing anti-tumor immunity, and reforming tumor microenvironment. Currently, CDK4/6 inhibitors have been confirmed to be effective in hormone-receptor-positive breast cancer and were approved as the first-line treatment for this breast cancer in combination with endocrine therapy. Furthermore, CDK4/6 inhibitors have been gradually applied to the treatment of other tumors, but the efficacy remains to be evaluated. Natural or acquired resistance to CDK4/6 inhibitors is a major factor affecting their efficacy. However, at present, only hormone receptor-positive (mainly estrogen receptor-positive) can relatively accurately predict the responsiveness of CDK4/6 inhibitors in combination with endo- crine treatment, and other markers need to be further explored and verified in clinical studies. The mechanism of action, the status of application, and mechanisms of drug-resistance of CDK4/6 inhibitors in the treatment of malignancies were reviewed and summarized in this paper, and the controversy over clinical decision-making on the treatment of breast cancer with CDK4/6 inhibitors was briefly discussed. -
脓毒症造成的弥散性血管内凝血(disseminated intravascular coagulation，DIC)是炎症与凝血系统相互作用的复杂病理生理过程。炎症小体是细胞溶质中的多蛋白复合物，也是人体免疫系统的重要组成部分，其活化能够介导细胞焦亡，从而导致质膜破裂(plasma membrane rupture，PMR)，使单核巨噬细胞过度释放白细胞介素(interleukin，IL)-1β、IL-18，产生炎症层联反应[1]，同时，血栓形成会导致凝血因子耗尽后的多器官功能性衰竭。本文就炎症小体与细胞焦亡之间的相关性及对凝血功能的影响相关研究进行综述，以期为DIC的临床治疗提供新思路。
1. 炎症小体与细胞焦亡
炎症小体由传感器、衔接子和效应子组成，其中起激活作用的典型传感器包括核苷酸结合结构域富含亮氨酸重复序列和含热蛋白结构域受体3 (nucleotide-binding domain leucine-rich repeat and pyrin domain-containing receptor 3，NLRP3)、NLRP1、核苷酸结合寡聚化结构域样受体蛋白4(NOD-like receptor family pyrin domain-containing protein 4，NLRC4)、热蛋白(pyrin) 和黑色素瘤缺乏因子2(absent in melanoma 2，AIM2)。NLRP3是目前研究较多的一类炎症小体，在中性粒细胞、单核细胞、树突状细胞、淋巴细胞中均有表达，其失调会导致过度炎症，并与自身炎症、自身免疫性疾病、代谢性疾病和肿瘤的发生密切相关[2-3]。研究表明，特异性表达NLRP3功能获得性突变体的高血糖模型小鼠出现肾损伤加重，主要表现为白蛋白尿增加、肾小球系膜扩张和肾小球基底膜厚度增加[4]，提示NLRP3的过度表达促进糖尿病肾病的发生发展。此外，NLRP3还会导致高血脂模型小鼠动脉粥样硬化，形成血栓[5]。
细胞焦亡是一种炎症性细胞死亡，主要发生在内皮细胞和巨噬细胞[6]。经典的细胞焦亡途径，其核心在于炎症小体的介导作用(图 1)，是指在病原体相关分子模式(pathogen-associated molecular patterns，PAMPs) 和损伤相关分子模式(damage-associated molecular patterns，DAMPs)的刺激下，炎症小体激活半胱天冬酶(caspase)-1，使成孔蛋白D(gasdermin D，GSDMD)水解释放N末端(N-terminal，NT)片段[7-9]，引起PMR并导致细胞焦亡，包括组织因子(tissue factor，TF)、乳酸脱氢酶(lactate dehydrogenase，LDH)等在内的细胞内容物被释放至细胞外，IL-1β和IL-18进一步攻击细胞，而脂多糖(lipopolysaccharide，LPS)等原胞质内物质暴露于组织中，通过caspase-11或caspase-4/5直接激活GSDMD，进一步诱导细胞焦亡，形成炎症层联反应[10-11]。
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图 1 炎症小体介导细胞焦亡的相关机制NLRP3(nucleotide-binding domain leucine-rich repeat and pyrin domain-containing receptor 3)：核苷酸结合结构域富含亮氨酸重复序列和含热蛋白结构域受体3；DsDNA(double-stranded DNA)：双链DNA；AIM2(absent in melanoma 2)：黑色素瘤缺乏因子2；PAMPs(pathogen-associated molecular patterns)：病原体相关分子模式；DAMPs(damage-associated molecular patterns)：损伤相关分子模式；NEK7(NIMA-related kinase 7)：NIMA相关激酶7；NLRP1(nucleotide-binding oligomerization domain-containing protein 1): 核苷酸结合寡聚化结构域样受体1；ROS(reactive oxygen species): 活性氧；IL(interleukin)：白细胞介素；GSDMD(gasdermin D)：成孔蛋白D；TF(tissue factor)：组织因子；LDH(lactate dehydrogenase)：乳酸脱氢酶; LPS(lipopolysaccharide): 脂多糖；TLR(Toll like receptor): Toll样受体Figure 1. Mechanisms related to inflammasome mediated cell pyroptosis2. 炎症反应与凝血功能
Davie等[12-13]发现凝血层联反应并证实外源性凝血系统由纤维蛋白原(fibrinogen，FⅠ)、凝血酶原(prothrombin，FⅡ)、TF和Ca2+组成。Hoffman等[14]提出一种基于细胞的凝血模型，将凝血阶段分为依赖性TF/Ⅶa启动(启动阶段，即外源性途径)、通过TF途径抑制物(tissue factor pathway inhibitor，TFPI)抑制TF/Ⅶa复合物、放大凝血酶生成(放大、扩增阶段，即内源性途径)。而凝血酶可通过激活血小板和内皮细胞表面的蛋白酶激活受体(protease activated receptors，PARS)，促进IL-6和IL-8的释放，并激活蛋白C，加剧炎症反应[15-16]。
抗凝血机制包括TFPI、肝素-抗凝血酶途径和蛋白C抗凝途径。其中，TFPI主要抑制外源性凝血途径，防止凝血级联反应的过度激活，从而避免血液在血管损伤部位以外的区域凝固[17]。肝素通过与抗凝血酶(antithrombin，AT)结合，促进AT对凝血酶和因子Ⅹa发挥抑制作用[18]。凝血酶与血管内皮细胞表面的血栓调节蛋白(thrombomodulin，TM)结合，会激活蛋白C抗凝途径，活化蛋白C(activated protein C，APC)能够与蛋白S结合，形成复合物，使因子Ⅴa和Ⅷa失活[19]。
Ryan等[20]研究发现，TF在细胞内表达后，其关键半胱氨酸残基发生修饰，使TF有效激活凝血途径。当PMR发生时，细胞中大量TF释放至血液中，在Ca2+的刺激下激活外源性凝血途径[21]。在炎症反应发生时，机体激活核因子κB(nuclear factor kappa-B，NF-κB)，促进TF基因表达，从而激活外源性凝血途径，促进血栓形成[22]。而TF和纤维蛋白原的表达升高，使得内皮细胞蛋白C受体(endothelial protein C receptor，EPCR)和α1-抗胰蛋白酶(α1-antitrypsin，α1-AT) 等抗凝蛋白表达降低，纤溶酶原激活剂抑制剂-1(plasminogen activator inhibitor 1，PAI-1)的活性受到抑制，导致凝血系统紊乱，增加血栓形成风险，并可能加剧疾病的严重程度[23]。当脓毒症发生时，TFPI的活性降低，IL-1β、肿瘤坏死因子-α(tumor necrosis factor-α，TNF-α)和内毒素可通过抑制基因转录下调血栓调节蛋白和EPCR，从而抑制蛋白C的活化[24-26]。综上，炎症反应不仅刺激内皮细胞及巨噬细胞分泌大量TF，激活外源性凝血途径(图 2)，还会影响凝血系统，导致血液处于高凝状态；反之，凝血因子表达上调会促进炎症因子分泌，说明炎症反应与凝血功能高度相关且相互影响。
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图 2 组织因子介导的凝血反应TF: 同图 1；Fibrin: 纤维蛋白；Platelet: 血小板；Prothrombin: 凝血酶原；Thrombin: 凝血酶Figure 2. Coagulation reaction mediated by tissue factor3. 炎症小体通过细胞焦亡影响凝血功能
研究表明，细胞焦亡通路中caspase-1及caspase-11的激活会导致巨噬细胞释放富含TF的细胞外囊泡[27-28]。在LPS的刺激下，单核细胞和内皮细胞通过炎症小体组装以及嘌呤能受体P2X7、caspase-1活化增加TF的表达，导致凝血反应发生[29]。caspase-11通过GSDMD触发Ca2+内流和跨膜蛋白16F的激活，增加TF的促凝血活性[30]。跨膜蛋白173可在炎症发生后通过细胞焦亡介导GSDMD裂解，并导致DIC的发生[31]。Wu等[32]利用革兰阴性菌的Ⅲ型分泌系统(type Ⅲ secretion system，T3SS)及LPS激活炎症小体，促使TF释放并以微泡形式进入血液循环，引发全身性凝血反应，导致实验动物死亡，该团队进一步敲除GSDMD后发现，缺乏GSDMD的细胞能够抵御细胞焦亡的发生，还能减少IL-1β和IL-18的分泌，证实炎症小体激活后释放TF依赖于细胞焦亡途径。
内皮细胞发生细胞焦亡可激活中性粒细胞胞外陷阱(neutrophil extracellular traps, NETs)[33-34]，NETs对宿主细胞具有极强的细胞毒性，可损伤和杀死内皮细胞，并导致凝血激活。NETs通过诱导内皮细胞释放黏附分子和TF以激活内皮细胞，随后招募炎症细胞并促进炎症和凝血反应的发生，而NETs中的中性粒细胞弹性蛋白酶和髓过氧化物酶通过蛋白水解裂解和抗凝血剂氧化上调促凝血反应[35]。此外，由于促血栓成分(如TF、血管性血友病因子、纤维连接蛋白、纤维蛋白原)的释放或表达以及膜抗凝成分的受损，受损或活化的内皮细胞呈现高凝状态[36]。补体系统在调节免疫反应中发挥重要作用，在细胞焦亡过程中，这些补体成分不仅触发凝血反应，且通过激活内皮细胞和血小板，进一步促进血液凝固。此外，细胞焦亡还通过上调PAI-1的表达，导致纤溶系统受损，使得血液凝固和血栓形成风险增加[37]。综上，炎症小体可通过激活细胞焦亡途径，释放TF囊泡并导致凝血功能紊乱，还可通过NETs及补体系统使血液处于高凝状态。
随着细胞焦亡机制相关研究的不断发展，NLRP3、GSDMD、caspase-1或可作为抗凝新靶点。研究表明，NLRP3抑制剂(MCC950)可有效阻断NLRP3炎症小体的激活[38]。双硫仑通过阻断GSDMD膜孔的形成可抑制细胞焦亡和细胞因子释放[39]。caspase-1抑制剂(VX-765)的衍生物(VRT-043198)可有效抑制IL-1β和IL-18的释放[40]。研究表明，败血梭菌是气性坏疽的主要病原体，其产生的α毒素会激活NLRP3，而MCC950可以阻断小鼠败血梭菌诱导的致死性[41]。在脓毒性休克患者中，VX-765可通过抑制B细胞亚群的选择性耗竭改善预后[42]。动物实验表明，在静脉血栓小鼠模型中，caspase-1的缺乏可防止流量限制诱导的血栓形成[43]。
4. 小结与展望
目前，脓毒症造成的凝血障碍及晚期不可逆性DIC是急危重症救治的一大难题。脓毒症的发生会促进NLRP3炎症小体生成以及caspase-1、caspase-11、GSDMD等蛋白表达，并导致细胞焦亡，促进IL-1β和IL-18的分泌，进一步加剧炎症反应，同时LPS、TF等激活外源性凝血途径，并通过NETs等途径抑制抗凝血机制，进一步耗竭凝血因子，增强凝血层联反应。细胞焦亡作为中心环节，可连接炎症小体的生成与外源性凝血途径，三者相互作用，共同使机体凝血达到不可逆状态，对脓毒症的治疗及预后造成了极大不确定性。因此通过抑制细胞焦亡机制干扰炎症反应的发展，同时减少TF的分泌，对于防止外源性凝血途径的激活具有重要意义。未来仍需针对细胞焦亡机制进行深入研究，为早期干预脓毒症，防止DIC的发生提供理论依据。
作者贡献:唐辉负责文献检索、数据分析、示意图绘制、论文撰写；应红艳参与文献检索、数据分析、论文修改；白春梅提供修改建议并帮助修改论文。利益冲突 无 -
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