2022, Vol. 49
2. 复旦大学肿瘤转移研究所 上海 200040
2. Cancer Metastasis Institute, Fudan University, Shanghai 200040, China
结直肠癌（colorectal cancer，CRC）是全球第三大常见癌症，也是第三大癌症相关死亡原因[1]。远处转移是导致CRC患者死亡最常见的原因，转移性结直肠癌（metastatic colorectal cancer，mCRC）患者5年生存率仅为13.8%[2]。长期以来，以化疗为基础的系统治疗在mCRC的综合治疗中占主导地位，患者中位总生存期在8~12个月[3-4]。2004年，靶向表皮生长因子受体（epidermal growth factor receptor，EGFR）药物西妥昔单抗的出现，标志着mCRC进入分子靶向治疗的时代。EGFR属于表皮生长因子受体家族，与配体结合后形成同源或异源二聚体，进而激活下游通路，诱导细胞增殖[5]。多项研究表明[6-7]，化疗联合抗EGFR治疗mCRC的总体生存（overall survival，OS）和无进展生存（progress free survival，PFS）均显著高于单纯化疗。
然而，抗EGFR治疗仅对部分RAS/RAF野生型的mCRC有效，RAS/RAF作为EGFR下游通路分子可介导EGFR的信号通路激活，引起对抗EGFR治疗耐药，初始RAS/RAF野生型mCRC在抗EGFR治疗的压力下，基因发生继发性突变可引起获得性耐药。最新的国内外指南已将KRAS、NRAS及BRAF状态作为指导抗EGFR治疗的重要标志物，也标志着mCRC的治疗理念向精准治疗转变。近期研究表明RAS和BRAF野生型患者依然可发生获得性抗EGFR耐药，有一半以上野生型患者不能从抗EGFR治疗中获益，仍存在抗EGFR治疗耐药的其他机制[8]。一方面，与mCRC发生发展相关的基因组学改变，使一部分RAS和BRAF野生型患者产生原发性耐药；另一方面，RAS和BRAF野生型患者在抗EGFR治疗过程中，其基因组发生改变可产生获得性耐药[9]；而最新研究表明治疗过程中肿瘤微环境（tumor microenvironment，TME）的重塑也可介导抗EGFR获得性耐药的发生[10]。因此，精准筛选抗EGFR治疗受益患者尤为重要。本文将从肿瘤细胞和肿瘤微环境两个方面，对mCRC抗EGFR治疗的耐药机制进行综述，为临床预防和逆转耐药策略提供借鉴。
肿瘤细胞自身基因组学改变介导的抗EGFR耐药
RTK-RAS信号通路 以EGFR为代表的受体酪氨酸激酶超家族及其下游的RAS-RAF信号通路是目前发现的最主要的抗EGFR治疗耐药机制（图 1）。除了经典的RAS及BRAF突变，介导抗EGFR耐药的基因组学改变可发生于该通路各个环节，包括配体、膜受体及下游信号转导分子。
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| 图 1 表皮生长因子受体（EGFR）信号通路和可能耐药机制 Fig 1 Epidermal growth factor receptor (EGFR) signaling pathway and potential mechanism of resistance |
AREG和EREG的低表达 双调蛋白（amphiregulin，AREG）和上皮调节蛋白（epiregulin，EREG）作为EGFR的配体，能诱导EGFR激活，进而通过RAS-RAF-MAPK和PI3K-AKT-mTOR通路促进肿瘤的发生和发展。研究表明，AREG和EREG的表达水平与抗EGFR治疗疗效密切相关，AREG和EREG高表达的患者预后更好[11-12]。有学者尝试调节AREG和EREG的水平以改善抗EGFR疗效，降低AREG/EREG启动子和基因内CpGs甲基化，使AREG和EREG基因表达上调，以达到临床获益[13]。
EGFR突变 EGFR胞外区域突变也是抗EGFR治疗耐药的潜在机制之一，Montagut等[14]发现EGFR ECD的S492R突变与抗EGFR治疗耐药相关，由于492位氨基酸的丝氨酸被精氨酸取代，位于EGFR胞外结构域的冗长侧链可干扰EGFR与西妥昔单抗的结合。与此同时，S492R突变只在经抗EGFR治疗的mCRC患者中检测到，可能是由于靶向治疗导致EGFR胞外区域的突变从而引起获得性耐药[15]。陆续有研究发现并确定了许多其他ECD突变（I462，S464，G465，K467，K489，I491），这些突变同样介导mCRC抗EGFR治疗的耐药[16-17]。一些新型抗EGFR疗法（Sym004和MM-151）可通过靶向EGFR ECD的不同位点来克服EGFR ECD突变引起的耐药[18-19]。
HER2扩增 人表皮因子生长受体（human epidermal growth factor receptor，HER2）是由HER2基因编码的一种酪氨酸激酶受体，与细胞增殖分化有关。HER2基因扩增发生于3%~5%的RAS野生型mCRC中，是抗EGFR治疗耐药的重要机制之一[20-21]。抗EGFR治疗耐药的KRAS野生型患者中，部分存在HER2扩增，且扩增个体肺转移率较高[20, 22]。多项研究揭示应用HER2抑制剂对该类患者疗效甚佳[23-24]。2016年HERACLES研究[23]结果显示，对经化疗联合抗EGFR治疗无效，KRAS野生型且HER2扩增的患者进行双靶向治疗（曲妥珠单抗+拉帕替尼），客观应答率（objective response rate，ORR）达30%且无严重不良反应。在MyPathway的研究[25]中，37例HER2扩增的转移性结直肠癌患者，经双靶向治疗（曲妥珠单抗+帕妥珠单抗）后取得部分缓解（partial response，PR）的有14例（38%；95%CI：23%~55%）。最近DESTINY-CRC01研究[26]显示，DS-8201（一种由曲妥珠单抗和拓扑异构酶Ⅰ抑制剂组成的抗体耦联药物）用于既往接受过标准治疗的HER2阳性的转移性CRC患者，取得临床获益且ORR达45.3%。HER2状态的评估为临床治疗决策提供了重要依据，HER2联合EGFR靶向治疗可能作为抗EGFR耐药患者的潜在治疗方案，但仍需要更多的临床试验进一步验证。
MET扩增 MET基因编码肝细胞生长因子（hepatocyte growth factor，HGF）的酪氨酸激酶受体（c-MET），c-MET可绕过RAS直接激活其下游MAPK和AKT通路，在多种肿瘤中均有致癌作用且与不良预后相关[27-28]。在未经治疗的mCRC患者中，仅有约1%存在MET扩增，与KRAS/BRAF突变以及HER2扩增呈互斥关系，且MET扩增的异种移植瘤对抗EGFR治疗无应答[29]。Bardelli等[29]发现MET扩增与KRAS野生型患者抗EGFR治疗的获得性耐药性有关，且体内体外实验证明抗EGFR治疗联合MET抑制剂可以逆转耐药，显著诱导肿瘤消退。
KRAS扩增 除热点突变外，KRAS扩增也是致癌机制之一。近期发现一小部分mCRC患者存在KRAS扩增，可能是导致患者耐药的原因[30]。有研究证实，KRAS扩增个体对抗EGFR治疗不敏感，与患者不良预后相关[30-31]。Favazza等[32]发现KRAS扩增的患者几乎均有炎症性肠病病史，8例接受了抗EGFR治疗，在治疗过程中均出现疾病进展，4例扩增且RAS/BRAF/PIK3CA野生型患者在接受西妥昔单抗治疗后均未获益。因此，KRAS扩增可能是EGFR抑制剂的潜在耐药机制。
MAP2K1突变 丝裂原活化蛋白激酶激酶1（mitogen-activated protein kinase kinase，MAP2K1）又称MEK1，是RAS和RAF下游的一种蛋白激酶，在细胞增殖和分化中起重要作用[33]。MAP2K1在mCRC患者中突变率为1%~2%，其中最常见的突变类型包括K57E/N/T和Q56P，可导致MAP2K1结构性激活[34-35]。前期有研究表明，MAP2K1突变是mCRC患者对EGFR抑制剂产生原发和继发耐药的潜在机制[9, 36]。Russo等[37]对接受抗EGFR治疗长期有效后发生肝转移的患者进行活检穿刺，发现该基因第57位密码子的赖氨酸被苏氨酸取代，且给予帕尼单抗联合曲美替尼治疗后取得疗效。Chuang等[38]发现联合MEK抑制剂可提高抗肿瘤疗效，但之后有2名患者经抗EGFR联合MEK抑制剂治疗后仍发生疾病进展。因此，MAP2K1突变通过激活下游通路，介导抗EGFR治疗耐药，而抗EGFR联合MEK抑制剂治疗可能对该类患者有效。
除上述耐药机制外，RTK-RAS通路中其他分子近年来也被证明与抗EGFR治疗耐药相关，有研究表明膜受体AXL过表达、EPHA2过表达以及NF1抑癌基因突变等与治疗耐药相关，均有可能成为潜在治疗靶点，但仍需进一步证实[10, 39-41]。
PI3K-AKT信号通路 在EGFR下游通路中，除了RAF-RAF-MEK通路外，PIK3/PIK3CA通路也参与了抗EGFR治疗的耐药（图 1）。
PIK3CA突变 PIK3CA突变在CRC中的发生率为10%~20%，主要发生在外显子9和20，引起PI3K下游的AKT/mTOR信号的激活[42]。研究表明，PIK3CA外显子20的突变与抗EGFR治疗低应答率有关[43]。PIK3CA外显子20突变与接受抗EGFR治疗的KRAS野生型mCRC患者的PFS和OS显著相关，KRAS/NRAS/BRAF/PIK3CA野生型的肿瘤患者的总有效率为64.4%，mPFS为11.3个月，任一基因发生突变都会使这两项指标降低（ORR 47.4%，mPFS 7.7个月）[44]。以上研究结果表明PIK3CA外显子20突变可以作为抗EGFR治疗耐药的潜在生物标志物，而外显子9与抗EGFR治疗耐药的相关性尚不明确。
PTEN缺失/突变 在PI3K-PTEN-AKT通路中，PTEN作为肿瘤抑制基因在肿瘤发生发展中发挥重要作用，PTEN缺失导致细胞内PI3K/AKT信号的持续激活[45]。PTEN缺失存在于30%的CRC患者中，且与抗EGFR治疗耐药有关[46]。Loupakis等[47]发现治疗有效患者的转移灶中PTEN阳性显著，提示PTEN状态可能是预测抗EGFR治疗疗效的指标。增强PTEN的功能可以通过增强其转录来实现，而转录的表观遗传沉默是由于启动子或组蛋白甲基化所致。早期研究报道了DNA甲基转移酶抑制剂地西他滨联合帕尼单抗治疗KRAS野生型患者的安全性[48-49]。
TGF-β通路
SMAD4突变 抑癌基因SMAD4是转化生长因子β（transforming growth factor-β，TGF-β）信号通路的关键分子，其失活突变可引起TGF-β通路的异常激活，约有10%的结直肠癌患者发生SMAD4基因突变且与预后不良相关[34, 50]。抗EGFR单抗的低反应性是由于TGF-β引起的MAPK/JNK信号通路过度激活而导致[51-52]。FIRE-3研究表明，SMAD4突变是预后不良的标志物之一，且SMAD4野生型个体经西妥昔单抗治疗的ORR更高，SMAD4突变可能为西妥昔单抗耐药提供依据[51, 53]。
非编码RNA 肿瘤细胞介导的抗EGFR耐药机制中，除了经典信号通路的基因组学改变外，以非编码RNA为代表的表观遗传学改变也是近年来发现的重要机制。
micro-RNA micro-RNAs（miRs）是在转录后水平控制基因表达的短链非编码RNA，参与细胞的发育和各项生理过程，并在肿瘤或炎症等病理条件下失调[54]。结直肠癌中，miRs的失调促进了肿瘤的发生、发展以及治疗耐药[55-56]。miRs不仅可作为肠癌早期诊断生物标志物，也是早期mCRC对抗EGFR单抗耐药的潜在决定因素[57]。
在mCRC中，miR-31通过抑制RAS-p21-GTP酶激活蛋白1来激活RAS信号通路，从而促进癌细胞的发生和生长，miR-31高表达与mCRC的疾病进展和不良预后相关，而miR-31-3p低表达患者在FOLFIRI联合西妥昔单抗治疗中获益[58-61]。Mosakhani等[62]检测了接受抗EGFR治疗的KRAS/BRAF野生型患者中原发灶的miRNA表达，发现miR-31、miR-140-5p上调和miR-592、miR-1224-5p下调与不良预后相关，miRNA图谱可以有效筛选患者进行个体化治疗。研究发现，miR-100和miR-125b的过表达与西妥昔单抗耐药有关，可协同抑制Wnt/β-catenin负调控因子，引起Wnt信号通路激活，且抑制Wnt信号通路可恢复对西妥昔单抗的反应[63]。
lncRNA 长链非编码（lncRNA）是长度大于200个核苷酸的非编码RNA，可通过结合miRs和蛋白质来影响mRNA翻译和基因的表达。研究表明，lncRNAs的失调与人类癌症相关[64-66]。lncRNA SNHG6通过与miR-26a、miR-26b和miR-214相互作用并调节它们共同的靶点EZH2，促进肠癌细胞的生长、迁移和侵袭[67]。体外实验表明，lncRNA CRNDE通过调控miR-181a-5p促进肠癌细胞的增殖和化疗耐药[68]。Peng等[69]发现9种lncRNA在疾病控制组和治疗无应答组之间表达存在差异，其中5种与患者PFS显著相关，进一步研究发现lncRNA POU5F1P4在获得性耐药细胞中和患者体内均下调，证明此基因下调促进了mCRC患者对西妥昔单抗的耐药性。lncRNA LINC00973在西妥昔单抗耐药细胞中的表达显著上调，敲低可改善H508细胞对西妥昔单抗的耐药性[70]。Yang等[71]研究发现，具有3个外显子的lncRNA尿路上皮癌相关1（UCA1）在西妥昔单抗耐药肠癌细胞及外泌体中表达明显增加，进展期患者UCA1表达明显高于病情缓解个体，且该lncRNA可通过外泌体传递至敏感细胞使其获得耐药性。lncRNA CRART16过表达可以下调miR-371a-5p来诱导西妥昔单抗耐药，进而负性调控V-Erb-B2红系白血病病毒同源基因3（ERBB3）的表达[72]。虽然介导抗EGFR治疗耐药的lncRNA被陆续发现，但是其耐药机制仍不明确。
其他机制
Src Src基因编码非受体酪氨酸激酶，约80%的CRC患者Src基因过表达，且与mCRC的发生密切相关[73]。有研究发现Src的激活介导了抗EGFR耐药的发生，耐药细胞株DiFi5存在Src介导的信号激活，Src抑制剂PP2可以对抗其耐药性[74]。但一项Ⅱ期临床试验研究显示FOLFOX与西妥昔单抗和达沙替尼联合使用对mCRC患者无明显获益，可能因为达沙替尼不能完全消除Src引起的磷酸化[75]。在肺癌和乳腺癌中Src抑制剂和抗EGFR联合治疗的临床试验在进行中且取得一定疗效，但是在mCRC中有待进一步证实。
FBXW7突变 抑癌基因FBXW7编码Skp1-Cullin1-F-box蛋白泛素E3连接酶复合物的底物识别成分[76]。E3连接酶复合体负向调节细胞内一系列关键致癌蛋白，因此，FBXW7功能缺失会引起胞内致癌蛋白积累，促进癌症发生发展[77]。在肠癌中，FBXW7突变发生率为6%~10%，其缺失与RAS激活和抗EGFR单抗耐药的基因表达谱相关[78]。研究表明，接受抗EGFR和化疗方案治疗的mCRC患者中耐药个体可发生FBXW7突变且治疗效果差[79-80]。在CAPRI-GOIM研究中，1例FBXW7突变患者PFS为18个月，另2例FBXW7突变患者对FOLFIRI联合西妥昔单抗治疗无应答，部分从靶向联合化疗方案中获益的FBXW7突变个体均存在GAS6基因扩增，可能因为GAS6过表达与良好预后相关[81-82]。
PRSS 丝氨酸蛋白酶由PRSS基因编码，可以断裂大分子蛋白质中的肽键。Tan等[83]研究发现，肠癌细胞自身分泌PRSS，降解西妥昔单抗从而介导耐药。西妥昔单抗耐药细胞中PRSS1表达上调，敲低PRSS1可以抑制PI3K/AKT和MEK/ERK信号的激活。SNINK1是一种胰蛋白酶抑制剂，体内外可显著抑制PRSS1对西妥昔单抗的降解，SPINK1与西妥昔单抗联合治疗比单用更能有效抑制癌细胞生长和p-ERK水平。mCRC患者血清中PRSS高水平与西妥昔单抗治疗无效密切相关，且PRSS1和PRSS3低表达个体PFS更长。因此PRSS高表达可能与抗EGFR治疗耐药相关，靶向治疗联合PRSS抑制剂是可行的选择。
基因组不稳定性 基因组不稳定性（genomic instability，GI）是指获得性基因突变率增加，与癌症发生发展密切相关[84]。Russo等[85]研究发现EGFR抑制剂可以下调耐药细胞中错配修复和同源重组修复基因，同时诱导低保真DNA聚合酶的合成，从而导致获得性耐药，且靶向治疗后患者肿瘤组织中MMR相关蛋白表达水平降低；同时发现，EGFR抑制剂可能通过增加癌细胞中活性氧的水平引起DNA损伤，微卫星不稳定性增加。另一项研究发现错配修复基因MLH1下调与不良预后相关，体外实验证明MLH1过表达可以增强耐药细胞的敏感性；进一步研究发现，MLH1缺失通过激活HER2/PI3K/AKT通路介导西妥昔单抗耐药，且阻断HER2信号增加微卫星不稳定型的敏感性，并在队列研究中得到验证[86]。综上所述，可利用药物或遗传干扰来抑制癌细胞发生药物驱动的适应性突变，以减少新变异的产生，增加靶向治疗的临床疗效。
肿瘤微环境重塑介导的抗EGFR耐药 尽管基因检测能筛查出抗EGFR治疗有效的患者，但大部分获得性耐药的患者中并未发现遗传驱动耐药的因素，近年来肿瘤微环境的改变成为耐药机制的研究热点[10, 87]。2015年国际结直肠癌分型联盟[88]提出了共识分子模型，根据不同病理特征将结直肠癌分为4种亚型：CMS1为微卫星不稳定型，又称为高突变型，表现为错配基因修复的改变；CMS2为经典型，与WNT和MYC信号通路异常激活有关；CMS3为代谢型，表现为KRAS突变程度高，代谢失调；CMS4为TGF-β信号通路异常激活。
肿瘤相关成纤维细胞介导 肿瘤相关的成纤维细胞（tumor associated fibroblasts，CAF）通过分泌生长因子和炎症介质，重塑细胞外基质，参与调解肿瘤细胞代谢及功能。Woolston等[10]研究发现转录组亚型的改变与获得性耐药关系密切，指出大部分出现疾病进展的患者从抗EGFR敏感的CMS2亚型转变为CMS4亚型。CMS4亚型富含CAF，是TGF-β和生长因子的主要来源。在CMS4中，TGF-β1和TGF-β2 RNA水平显著增加，且CAF条件培养基（CAF medium，CM）培养CRC干细胞可以使其获得耐药性，用重组FGF1、FGF2和HGF处理，在西妥昔单抗暴露下癌细胞正常生长，且西妥昔单抗、FGFRi和MET抑制剂三药联用可有效抑制癌细胞生长，证实了CAF介导基质重塑在非遗传性耐药中的重要作用。另两项研究表明，在使用西妥昔单抗治疗后，CAF分泌的EGF和HGF增加，分别激活MAPK、MET信号通路，且双靶点治疗有助于克服耐药性[89-90]。因此，在抗EGFR过程中，肿瘤微环境中CAF丰度增加，导致其分泌生长因子增加，从而引起获得性耐药，调节微环境中CAF丰度或其分泌的细胞因子可能成为新的治疗策略。
炎症细胞介导 体外研究显示，耐药细胞系中外周血单个核细胞产生的炎症因子，包括IL-1A、IL-1B和IL-8，均与EGFR治疗耐药相关。当肿瘤微环境中IL-1增加，IL-1与肿瘤细胞表面相应受体结合，继发性激活EGFR通路，来维持胞内ERK和AKT的信号[91-92]。抑制该类细胞因子的产生可能是EGFR单抗耐药患者的有效治疗策略。研究表明，高水平表达IL-1受体（IL-1R）的患者对西妥昔单抗治疗无效[92]。此外，接受西妥昔单抗联合化疗的患者在治疗后外周血发生细胞因子改变（IL-2、IFN-γ、IL-12和IL-18增加，IL-4和IL-10减少），提示与治疗反应相关，表明监测外周免疫系统可作为预测患者治疗疗效的参考[93-94]。
结语 肿瘤基因组的高度异质性和不稳定性，是引起mCRC抗EGFR治疗耐药的重要原因。而传统的RAS和BRAF基因检测已无法满足肿瘤精准治疗的要求。下一代测序技术（next generation sequencing，NGS）的逐渐普及，有利于检出低突变频率的耐药基因突变；而液体活检技术的不断发展，可在抗EGFR治疗期间对ctDNA进行监测，及时发现耐药基因突变。针对耐药突变进行多靶点联合的个体化治疗策略显示了广阔的前景。近年来，EGFR单抗联合其他靶向治疗的临床研究取得了积极进展（表 1），已有部分临床试验通过尝试联合其他靶点治疗从而克服抗EGFR治疗耐药，且取得了阳性结果。另一方面，肿瘤微环境的重塑与抗EGFR治疗耐药之间也存在密切关系，靶向微环境中细胞因子有望成为治疗抗EGFR耐药患者的新策略。
| Study | NCT number | Recruitment Details | Treatment | Phase | Status |
| BEACON[95] | NCT02928224 | BRAF V600E-mutant mCRC | Dabrafenib+trametinib+panitumumab | Ⅲ | Completed |
| SWOG S1406[96] | NCT02164916 | BRAF V600E-mutant mCRC | Irinotecan+cetuximab+vemurafenib | Ⅱ | Completed |
| KRYSTAL-1 | NCT03785249 | KRAS G12C-mutant mCRC | Adagrasib+cetuximab | Ⅰ/Ⅱ | Active |
| Codebreak101 | NCT04185883 | KRAS G12C-mutant mCRC | Sotorasib+ panitumumab | Ⅰ/Ⅱ | Active |
| -[97] | NCT01287130 | KRAS mutant mCRC | Selumetinib+cetuximab | Ⅰ | Completed |
| -[98] | NCT02205398 | MET positive mCRC | Capmatinib+cetuximab | Ⅰ | Terminated |
| -[99] | NCT01075048 | MET positive mCRC | Tivantinib+cetuximab | Ⅱ | Completed |
作者贡献声明 韩佳澔 文献收集，绘图，论文撰写和修订。王祥宇 论文撰写和审阅，制表。张冲 论文写作指导。陈进宏 论文修订和审校。
利益冲突声明 所有作者均声明不存在利益冲突。
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