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Journal of Central South University Medical Sciences logoLink to Journal of Central South University Medical Sciences
. 2021 May 28;46(5):545–551. [Article in Chinese] doi: 10.11817/j.issn.1672-7347.2021.200529

代谢重编程在非小细胞肺癌表皮生长因子受体酪氨酸激酶抑制剂耐药中的作用

Role of metabolic reprogramming in drug resistance to epidermal growth factor tyrosine kinase inhibitors in non-small cell lung cancer

WU Yu 1,1, GAO Wei 1,✉, LIU Hao 1,✉
Editor: 傅 希文
PMCID: PMC10930213  PMID: 34148892

Abstract

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) can effectively inhibit the growth of EGFR-dependent mutant non-small cell lung cancer (NSCLC). Unfortunately, NSCLC patients often develop severe drug resistance after long-term EGFR-TKI treatment. Studies have shown that the disorder of energy metabolism in tumor cells can induce EGFR-TKI resistance. Due to the drug action, gene mutation and other factors, tumor cells undergo metabolic reprogramming, which increases the metabolic rate and intensity of tumor cells, promotes the intake and synthesis of nutrients (such as sugar, fat and glutamine), forms a microenvironment conducive to tumor growth, enhances the bypass activation, phenotype transformation and abnormal proliferation of tumor cells, and inhibits the activity of immune cells and apoptosis of tumor cells, ultimately leading to drug resistance of tumor cells to EGFR-TKI. Therefore, targeting energy metabolism of NSCLC may be a potential way to alleviate TKI resistance.

Keywords: epiderinal growth factor receptor tyrosine kinase inhibitor, non-small cell lung cancer, tumor metabolism reprogramming, drug resistance

肺癌是全球发病率和病死率最高的癌症类型。近年来我国的肺癌发病率和病死率急剧飙升，严重危害国民的健康[1]。非小细胞肺癌(non-small cell lung cancer，NSCLC)约占肺癌的85%，起病隐匿，发展迅速，多数患者在确诊时已处于中晚期，预后极差。有40%~50%的NSCLC患者会出现表皮生长因子受体(epidermal growth factor receptor，EGFR)突变[2-3]。EGFR基因突变导致的受体结构变化会引起其下游信号通路的磷酸化活化，继而通过一系列复杂的机制最终导致肺癌的发生[4]。传统的NSCLC治疗方法是以放射治疗(以下简称放疗)和铂类化合物化学治疗(以下简称化疗)为主并伴随其他非靶向药物为辅的联合疗法。近年来随着精准医疗的发展，酪氨酸激酶抑制剂(tyrosine kinase inhibitor，TKI)逐渐成为治疗EGFR突变型NSCLC的首选药物[5]。然而，多数NSCLC患者在接受10个月以上的EGFR-TKI治疗后出现严重的耐药性，患者在耐药发生后无法进行靶向治疗[6]。EGFR-TKI继发性耐药的机制涉及许多方面：1)EGFR基因突变，如T790M突变、C797S突变、20ins插入突变等[7-8]。2)旁路异常激活以及间质表皮转化因子(mesenchymal to epithelial transition factor，MET)、人表皮生长因子受体-2(human epidermal growth factor receptor，HER-2)等基因扩增或者突变[9-10]。3)下游信号通路异常激活，如大鼠肉瘤(rat sarcoma，RAS)基因、磷脂酰肌醇-4，5-二磷酸3-激酶催化亚单位α (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha，PIK3CA)基因突变介导的下游信号通路激活等[11-12]。4)其他机制。①抑癌基因失活，如磷酸酯酶与张力蛋白同源物(phosphatase and tensin homolog，PTEN)基因、F框/WD-40域蛋白7(F-box and WD-40 domain protein 7，FBXW7)基因下调[13-14]；②NSCLC组织学类型改变，如上皮-间质转化或者小细胞肺癌转化等[15]；③致癌基因融合，如间变性淋巴瘤激酶(anaplastic lymphoma kinase，ALK)基因融合[16]。但由于其耐药机制复杂多变，很多耐药的发生并非单一的原因导致的，约有40%的耐药是由多种因素引起的，且仍有20%的获得性耐药机制并不十分明确，给EGFR-TKI的临床实际应用带来了困难。有研究[17]显示：肿瘤细胞代谢(如糖、脂质、谷氨酰胺等)的紊乱会从基因表达的多个水平影响到肿瘤细胞的增殖生长和衰老凋亡等，这可能是引起TKI耐药的重要因素之一。笔者主要就EGFR-TKI耐药与NSCLC细胞代谢之间的关系进行综述，探讨通过干预NSCLC细胞能量代谢途径来缓解或者逆转EGFR-TKI耐药的有效思路和方法。

1. EGFR-TKI耐药与NSCLC细胞代谢

1.1. 糖代谢

EGFR敏感性突变会显著上调NSCLC细胞糖酵解和磷酸戊糖途径关键蛋白[如葡萄糖转运体(glucose transporters，GLUTs)、磷酸果糖激酶-1(phospho-fructokinase-1，PFK-1)等]的表达和代谢产物[如乳酸(lactic acid，LA)、5-磷酸核糖(ribose 5-phosphate，R5P)等]的合成，继而引起细胞内糖代谢异常和缺氧环境的形成[18-19]。

外界因素或者基因突变导致的细胞内多种变化(如缺氧、生长因子和激素释放、代谢产物堆积和信号通路激活等)都会影响糖代谢相关基因的表达。研究[20-22]表明：磷脂酰肌醇-3激酶(phosphatidylinositol-3 kinase，PI3K)/蛋白激酶B(protein kinase B，Akt)信号通路激活参与了调控糖代谢相关基因的表达。肿瘤细胞可通过PI3K/AKT信号通路调节GLUTs从细胞内膜到外膜表面转移，增加细胞葡萄糖的摄取。另有研究[23-24]发现：吉非替尼可以下调EGFR敏感突变NSCLC细胞中GLUTs的表达，而对吉非替尼耐药的NSCLC细胞中GLUTs受体表达水平和葡萄糖摄入量均升高。还有研究[25]发现：活化的柯尔斯顿大鼠肉瘤病毒癌基因同源物4A(Kirsten rat sarcoma viral oncogene homolog 4A，K-RAS4A)蛋白能直接与己糖激酶1(hexokinase 1，HK1)结合，并形成复合体定位在线粒体外膜上，对肿瘤细胞的糖代谢产生重要的影响。上述研究表明：发生EGFR基因突变的NSCLC细胞的糖酵解受到多种因素的调节，且与EGFR-TKI耐药的发生关系密切。

有氧糖酵解引起的代谢产物堆积和酸性环境介导了NSCLC细胞和非癌细胞之间的交互作用，能够促进EGFR-TKI耐药的发生。如癌症相关成纤维细胞可通过摄取大量乳酸，在核因子-κB(nuclear factor-κB，NF-κB)的参与下诱导肝细胞生长因子(hepatocyte growth factor，HGF)过度表达，继而激活细胞间质表皮转化因子(cellular-mesenchymal to epithelial transition factor，c-MET)信号通路，导致NSCLC细胞产生非依赖于EGFR的TKI耐药[26-27]；又如肿瘤细胞周围的基质细胞在有氧糖酵解环境刺激下能够分泌一系列调控肿瘤增殖生长和衰老凋亡的信号分子，如表皮生长因子(epidermal growth factor，EGF)以及各种细胞因子、趋化因子等。肿瘤细胞由于持续处于缺氧环境中，因此其缺氧诱导因子-1(hypoxia inducible factor-1，HIF-1α)常常呈高表达。有研究[28]表明：EGF通过EGFR/PI3K/HIF-1α轴协同糖酵解而促进上皮间质转化过程，最终导致NSCLC细胞对TKI敏感性的下降。此外，有氧糖酵解产生的大量代谢物会促进肿瘤免疫抑制性微环境的形成，最终促进肿瘤细胞的免疫逃逸，从而降低细胞对TKI的敏感性。

1.2. 谷氨酰胺代谢

谷氨酰胺是NSCLC细胞不可或缺的营养物质。谷氨酰胺在多种酶的催化下分解并转化为α-酮戊二酸进入三羧酸循环中，继而通过呼吸链的氧化还原反应为细胞的生命活动提供能量。此外，谷氨酰胺还参与细胞中的核苷酸、脂质和氨基酸等的生物合成，为细胞稳定的碳源和氮源，还可转化为还原性谷胱甘肽，降低细胞内的活性氧(reactive oxygen species，ROS)水平，以维持细胞内的氧化还原平衡[29]。

EGFR敏感性突变会导致NSCLC细胞中的谷氨酰胺代谢关键蛋白上调，以及脯氨酸、天冬氨酸、还原性烟酰胺腺嘌呤二核苷酸(nicotinamide adenine dinucleotide, NADH)、丙酮酸和还原性谷胱甘肽等产物水平上调。研究[30]表明：肿瘤细胞可通过不同的机制调控促增殖生长信号通路的激活，继而上调谷氨酰胺的利用来驱动核苷酸、脂质和氨基酸的生物合成，如PI3K/Akt和KRAS下游通路的激活能促进肿瘤细胞谷氨酰胺代谢。另有研究[31]表明：PIK3CA突变会导致谷丙转氨酶2(glutamic pyruvic transaminase 2，GPT2)的高表达，上调谷氨酸盐转化为丙酮酸盐的速率，促进丙氨酸的合成。此外，哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin，mTOR)激活能上调天冬氨酸转代谢相关酶水平，催化谷氨酰胺分解转化而进入核苷酸前体的合成。在物质能量匮乏的情况下，肿瘤细胞能通过自噬获取谷氨酰胺，如RAS基因突变能驱动NSCLC细胞发生自噬，从而促使肿瘤细胞获取包括谷氨酰胺在内的必需物质[32]。而发生HER2扩增的NSCLC细胞则可通过细胞-骨髓细胞瘤病毒癌基因(cellular-myelocytomatosis-viral oncogene，c-Myc)/NF-κB途径促进谷氨酰胺代谢相关酶和转运体的表达。转化生长因子-β(trans-forming growth factor-β，TGF-β)-无翅型小鼠乳腺肿瘤病毒整合位点基因(wingless type mouse mammary tumor virus integration site gene，WNT)上调会促进锌指转录因子蜗牛锌指转录因子(snail zine-finger transcription factors，SNAIL)和同源盒转录因子2(distal-less homeobox 2，DLX2)的激活，从而上调谷氨酰胺酶(glutaminase，GLS)水平，同时促使肿瘤细胞发生上皮间质转化。发生PTEN下调或者缺失的NSCLC细胞会降低GLS的泛素化，间接促进谷氨酰胺代谢[29]。

1.3. 脂质代谢

脂质的代谢对细胞内环境稳态具有重要的作用，脂质代谢紊乱会促进肿瘤的发生。细胞一般通过自身的从头合成或外泌体转运方式获得包括三酰甘油、脂肪酸、磷脂、胆固醇、前列腺素和鞘脂在内的多种脂质。脂质在线粒体中通过β氧化途径被氧化而产生能量，还为生物膜、激素、信号分子的合成提供原料或者以脂滴或脂蛋白形式储存在细胞中[33-34]。

NSCLC细胞的EGFR信号通路被激活后会上调多种脂质代谢关键酶表达，促进肿瘤细胞的脂质代谢重编程[35-36]。脂质信号分子是由脂质参与组成的具有信号传递功能的生物分子，可与细胞膜或者胞内多种受体结合而传递各种信号[37]。脂质信号分子能够反向激活EGFR下游的信号通路，从而拮抗EGFR-TKI的治疗效果，诱导TKI耐药的产生。研究[38]显示：前列腺素E2(prostaglandin E2，PGE2)可通过细胞内机制反向激活EGFR/PI3K/Akt信号通路。另一项研究[39]显示：白三烯(leukotriene，LT)可通过激活PI3K/Akt信号通路而诱导肿瘤细胞增殖和迁移。NSCLC细胞高表达脂肪酸合成酶(fatty acid synthetase，FASN)，其产物16C饱和脂肪酸棕榈酸酯通过对EGFR棕榈酰化能够激活其下游信号通路介导的TKI获得性耐药[40]。NSCLC细胞高表达硬脂酰辅酶A去饱和酶-1(stearyl coenzyme A dehydrogenase-1，SCD-1)可引起胆固醇累积，促进EGFR、AKT、丝裂原活化蛋白激酶激酶(mitogen-activated protein kinase kinase，MAPKK)和细胞外调节蛋白激酶(extracellular regulated protein kinases，ERK)1/2的磷酸化，激活PI3K/Akt/mTOR信号通路，从而降低TKI介导的细胞凋亡[41]。此外，胆固醇还能够增加脂肪细胞膜关联蛋白(recombinant adipocyte plasma membrane associated protein，APMAP)蛋白和EGFR配体蛋白之间的相互作用，抑制胆固醇介导的EGFR降解作用，诱导肿瘤细胞发生上皮间质转化，最终导致NSCLC对TKI产生耐药性[42]。

2. 肿瘤细胞能量代谢的调控靶点

2.1. 活化转录因子4

c-Myc蛋白是一种核转录因子，是位于EGFR信号通路下游的信号分子，可与核内DNA特异性结合，影响多种基因的表达。c-Myc基因参与调控多种细胞代谢途径[43-46]，包括脂质代谢、谷氨酰胺代谢和糖代谢等。通过靶向c-Myc通路的下游蛋白活化转录因子4(activating transcription factor 4，ATF4)可显著抑制肿瘤的生长。ATF4蛋白作为c-Myc的下游蛋白，可调控细胞多种基因的表达。这些基因多与肿瘤细胞的糖酵解、氨基酸代谢、氧化磷酸化反应和脂肪酸合成等有关。因此，靶向ATF4蛋白有望成为一个干预EGFR-TKI耐药的可行措施。

2.2. 乳酸脱氢酶

乳酸在EGFR-TKI耐药中扮演了重要的角色[47-48]。乳酸堆积能够诱导各种非癌细胞分泌细胞因子、转录因子和激素等，继而与肿瘤细胞产生交互作用，激活相应的受体或者信号通路而造成NSCLC细胞免疫抑制、表型转化或者旁路激活等。发生EGFR突变的NSCLC细胞能通过c-Myc上调乳酸脱氢酶(lactate dehydrogenase，LDH)基因的表达，造成乳酸大量堆积[49]。因此，可通过抑制LDH 来干预NSCLC代谢重编程引起的EGFR-TKI耐药。

2.3. 葡萄糖-6-磷酸脱氢酶

核糖5磷酸是DNA和RNA合成的必需原料，其合成主要通过磷酸戊糖途径[50]。肿瘤细胞的旺盛分裂需要充足的核苷酸来合成遗传物质和大量的NADH来维持氧化还原平衡，以降低细胞内的ROS水平。NSCLC细胞发生EGFR突变后能促进磷酸戊糖途径，增加核糖5磷酸和NADH的产量。葡萄糖-6-磷酸脱氢酶(glucose-6-phosphate dehydrogenase，G6PDH)是磷酸戊糖途径的关键酶，目前的研究[51]都尝试以G6PDH为靶点来抑制肿瘤的生长。因此，G6PDH可作为一个缓解NSCLC细胞TKI耐药的潜在靶点。

2.4. GLS

GLS是谷氨酰胺代谢的关键酶。细胞的线粒体和胞质中均存在不同亚型的GLS，这些酶分别参与催化不同的生物合成过程。大量证据[52-53]显示：发生EGFR-TKI耐药的NSCLC细胞中的谷氨酰胺水平显著上调。因此，通过削弱GLS的活性能够有效削弱肿瘤细胞代谢重编程，减少TKI耐药的发生。CB-839是一种选择性抑制GLS的化合物，能够显著地降低肿瘤细胞谷氨酰胺的摄入，有效抑制NSCLC细胞的增殖和存活，可作为一个干预TKI耐药的潜在药物[54]。

2.5. FASN

FASN是脂肪酸合成的关键酶。研究[55]表明：发生EGFR-TKI耐药突变的NSCLC细胞中FASN水平显著上调。抑制FASN活性能明显减弱NSCLC细胞的脂质代谢异常，并下调腺嘌呤核苷三磷酸 (adenosine triphosphate，ATP)水平而抑制肿瘤的增殖和生长。因此，FASN可作为一个干预NSCLC细胞EGFR-TKI耐药的潜在靶点。

2.6. 甾醇调节元件结合蛋白

甾醇调节元件结合蛋白-1(sterol regulatory element- binding protein 1，SREBP-1)可在转录水平上影响脂质的生物合成，有SREBP-1a和SREBP-1c两种亚型。SREBP-1能调控包括FASN和SCD-1等与脂质合成相关酶基因的表达[56]。因此，抑制癌细胞中的SREBP-1可以下调脂质的积累和脂质信号分子的表达，降低脂质代谢重编程，使得NSCLC耐药细胞重新获得对EGFR-TKI的敏感性。氢溴酸盐是一种特异性的SREBP抑制剂，能够显著地抑制SREBP-1和SREBP-2的活性[57]。

3. EGFR-TKI耐药的治疗思路

随着EGFR-TKI的广泛运用，耐药问题日益严重，NSCLC患者常常面临无特效药可用的局面。EGFR-TKI虽然具有较好的临床治疗效果，但通过直接抑制NSCLC细胞单一靶点难以发挥长久的抗肿瘤效果。晚期NSCLC患者由于其体质虚弱、免疫低下，一旦发生耐药后，可选择的治疗方案非常有限。中药具有成分多、靶点多、药性温和等优点，主要通过纠正异常的细胞代谢、调节机体内环境平衡而增强免疫，发挥药效。现已成为肿瘤治疗的重要辅助手段之一。茶多酚没食子儿茶素是从绿茶中分离的一种多酚类黄酮，因其能抑制端粒酶和DNA甲基转移酶，阻滞EGF受体和HER-2受体的激活，抑制脂肪酸合成酶以及谷氨酸脱氢酶的活性[58]，所以在理论上能够在一定程度上纠正NSCLC细胞代谢的紊乱，抑制代谢重编程，具有潜在的缓解或逆转EGFR-TKI耐药的作用。清热解毒药半枝莲主要成份有黄酮、二萜类化合物等，具有抗癌、抗血管生成、增强免疫力、祛痰等作用[59]。因此，EGFR-TKI与具有代谢抑制作用的中药联合运用可能是缓解或者逆转EGFR-TKI耐药的一个有效思路。

4. 展 望

NSCLC细胞TKI耐药的机制十分复杂，通常是多种因素相互交替作用的结果。肿瘤细胞需要大量不同来源的能量和营养物质以满足从癌变发生到进展再到转移的高合成代谢需求。EGFR敏感性突变的确会造成肿瘤细胞代谢重编程，如有氧糖酵解和磷酸戊糖途径增强、谷氨酰胺代谢水平上调、脂质和腺苷合成增加、线粒体功能失调、氧化磷酸化受到削弱、ATP合成上调等。肿瘤细胞的代谢反应除了为其自身生长活动提供充足的能量外，还造成了大量代谢物的积累。这些代谢物除了为肿瘤生物合成提供原料外，还能通过多种渠道激活不同的信号通路，在各种细胞因子、趋化因子、转录因子、酶和受体蛋白的参与下从基因表达的不同水平促进肿瘤细胞的免疫抑制、旁路激活、氧化供能途径改变和细胞组织学改变等，继而促进EGFR-TKI耐药的发生。此外，肿瘤组织周围常生长着大量的非肿瘤细胞(如免疫细胞、脂肪细胞)等，这些细胞的活动及其分泌的各种细胞因子、激素等也会对NSCLC细胞的多种基因表达产生影响，促进EGFR-TKI耐药的发生。目前对于NSCLC细胞TKI耐药的机制仍然存在较多的未知，随着TKI耐药机制和NSCLC细胞代谢调控网络之间关系的逐渐阐明，相信在不久的将来能够成功地克服TKI耐药这一难题。

基金资助

国家“重大新药创制”科技重大专项(2019ZX09303001)；安徽省科技重大专项(201903a07020029)；安徽省学术技术带头人及后备人选科研活动经费(2019H215)。

This work was supported by the Major Scientific and Technological Projects of the National “Major New Drug Discovery” (2019ZX09303001), the Major Science and Technology Projects in Anhui Province (201903a07020029), and the Funds for Scientific Research Activities of Academic and Technological Leaders and Reserve Candidates in Anhui Province (2019H215), China.

利益冲突声明

作者声称无任何利益冲突。

原文网址

http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/202105545.pdf

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