ER阳性乳腺癌常见治疗药物的耐药性和相关应对策略_乳腺癌

ER阳性乳腺癌常见治疗药物的耐药性和相关应对策略

2025-12-17

关键词：乳腺癌

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乳腺癌是女性发病率居首位的恶性肿瘤，雌激素受体阳性（ER+）乳腺癌是其主要亚型之一。雌激素在ER+乳腺癌的发生和发展中发挥重要的作用，内分泌治疗（ET）可以降低患者雌激素水平或调节雌激素，进而发挥治疗作用。然而在实际治疗中，由于基因突变、微小RNA（miRNA）变异、表观遗传修饰等遗传学差异的存在，往往会导致乳腺癌细胞对常见的治疗药物产生耐药。因此，深入了解ER阳性乳腺癌常见治疗药物的作用机制及耐药发生机制，并针对性地发掘如光动力疗法、COX2抑制剂、miRNA1246抑制剂等应新型治疗策略，将为乳腺癌的治疗带来更多可能¹。

乳腺癌是女性最常见的恶性肿瘤，约占女性所有恶性肿瘤的24.5%²。ER 表达异常是激素依赖性乳腺癌发生发展的主要因素，其主要的常规治疗方法是内分泌治疗，包括选择性雌激素受体调节剂（SERMS）、选择性雌激素受体降解剂（SERD）、芳香化酶抑制剂（AI）、卵巢功能抑制（OFS）等³。

SERM包括他莫昔芬、托瑞米芬、雷洛昔芬等。他莫昔芬可竞争性抑制雌激素E2对雌激素受体结构域AF2的介导调节作用，发挥对ER的拮抗作用，同时仍保留一些部分激动作用⁴。他莫昔芬对雌激素调节基因的抑制可使细胞周期阻滞在G1期，最终导致程序性细胞死亡⁵。托瑞米芬是他莫昔芬的氯化衍生物，作用机制与他莫昔芬类似。雷洛昔芬同样可以与ER竞争性结合，并通过ER靶基因募集共激活因子和共阻遏因子发挥激动或拮抗作用⁶。SERD的代表性药物是氟维司群，其可通过与ER单体结合以抑制ER二聚化，一方面可以使AF1、AF2失活，导致ER对细胞核定位降低；另一方面氟维司群与ER复合物不稳定，可促进ER降解并降低ER水平⁷。AI的常用药之一是来曲唑，可通过与细胞色素P450竞争性结合来阻碍芳香化酶活性，从而抑制所有组织中的雌激素合成，阻止肿瘤生长^8,9。

图1.常见的内分泌治疗药物

由于基因突变、miRNA变异、表观遗传变异等因素的存在，会导致乳腺癌患者对上述常见内分泌治疗药物出现原发性耐药或继发性耐药，进而影响预后。在基因突变方面，ABCB1基因可编码P-糖蛋白（P-gp），是ATP结合盒转运蛋白（ABC）关键编码基因之一。P-gp可通过使用ATP将药物转运至细胞外，如ABCB1、COX2等相关基因突变会增加药物外排，造成多种药物耐药（MDR）^10,11。AKT过度激活会影响多个通路造成耐药。PI3K/AKT/mTOR通路与细胞的代谢、增殖密切相关，相关基因突变使之过度激活并造成耐药，该通路关键核心位点即为AKT¹²。再者，AKT还会与Notch、NF-κB、Snt/β-catenin、MAP等通路相互作用产生耐药¹³。S100A8/A9 基因高表达则会导致ESR1下调，导致SERM耐药¹⁴。TAGLN2基因过表达和NPM多态性上调则会使PTEN表达失调，过度激活PI3K/AKT通路，并使ABC增加，造成耐药和肿瘤侵袭性增强^15,16。

图2.乳腺癌耐药相关基因

miRNA负责调节基因表达，其表达异常与乳腺癌增殖、转移及耐药相关。如miR-33a的表达会引起氟维司群耐药¹⁷；miRNA-27b是一种抑癌因子，可通过促进p53细胞凋亡途径以提升抗癌治疗效果，该基因下调则会导致化疗药物耐药¹⁸；低水平miR-298会导致P-gp mRNA表达相关，从而导致多柔比星耐药¹⁹；miR-1246一般存在于正常组织中，在正常组织细胞癌变时会进入血液循环中，miR-1246升高会降低乳腺癌中抑癌基因CCNG2水平，导致肿瘤恶化²⁰；此外，miRNA-3130、miRNA-548、miR-92a、miR-427可能也与乳腺癌的发展及耐药相关²¹。

表观遗传机制的改变可能导致基因错误表达，致使癌症进展。乳腺癌细胞中DOC7高甲基化、CTCF高甲基化可能造成他莫昔芬耐药^22,23 。组蛋白3的乙酰化会导致DNA错配修复（MMR）功能丧失，从而使多柔比星等多重耐药发生²⁴。

现阶段检测乳腺癌相关耐药变异的方法包括数字聚合酶链反应（PCR）、下一代基因测序（NGS）、染色质免疫共沉淀（ChIP）、电化学生物传感器等。通过深入认识乳腺癌耐药机制，精准检测相关生物标志物，将有助于针对性开发新的克服耐药策略。首先，光动力疗法（PDT）是针对乳腺癌耐药的最新研发技术之一，通过使用光敏剂靶向ABC转运蛋白，从而减少药物外排并提升内分泌治疗疗效²⁵。虽然肿瘤细胞中高谷胱甘肽水平可能导致PDT疗效降低，但正在开发的PDT与线粒体复合物Ⅲ抑制剂等形成的自递送纳米棒（AINR）技术可以克服该作用，并在TNBC中得到了初步验证²⁶。再者，Guajadial和 talazoparib可通过靶向ABC转运蛋白基因而克服乳腺癌耐药，具有一定开发潜力^27,28。针对miRNA变异引起的耐药性，miRNA抑制剂或激活剂可能具有克服耐药的作用。此外，对于CYP2D6介导的内分泌耐药，大麻二酚可抑制CYP3A4和CYP2D6，进而可减少他莫昔芬的代谢，提高疗效²⁹。

图3.PDT、Guajadial、Talazoparib、大麻二酚的作用机制

长久以来，SERM、SERD、AI等内分泌治疗手段改善了乳腺癌患者的预后，但由于基因突变、miRNA变异、表观遗传学变化，仍会引起原发或继发性耐药，导致疾病进展。因此，通过新型的检测手段识别耐药相关生物标志物，深入理解耐药机制，并针对性地开发相应治疗药物，将为乳腺癌患者带来更多、更好的治疗策略。

本材料由阿斯利康提供，仅供医疗卫生专业人士参考

审批编号：CN-160180

过期日期：2026-12-11

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