肺癌黄金靶点ALK靶向治疗的耐药问题

2024.09.30 责任编辑:陈醒 阅读量:211

ALK 的靶向治疗

目前在国内外获批的针对 ALK 的小分子酪氨酸酶抑制剂(TKI)有6种,可分为三代。
ALK 的靶向治疗

ALK-TKI 靶向治疗的耐药问题

对 ALK 靶向治疗的耐药性可大致分为 ALK 依赖性和 ALK 非依赖性两类。ALK 依赖性或“在靶”耐药性主要由 ALK 基因中出现的单个或复合突变引起,使肿瘤细胞持续依赖 ALK 活性。ALK 非依赖性或“脱靶”耐药定义为谱系变化或 ALK 非依赖性信号通路的激活,从而消除了 ALK⁺ 肿瘤细胞中的 ALK 依赖性。
肺癌黄金靶点ALK靶向治疗的耐药问题
ALK 依赖性耐药
在 50-60% 接受第二代 ALK 抑制剂治疗的患者中,耐药性是通过获得继发性 ALK 突变而产生的[14]。这些突变普遍发生在激酶结构域中,并通过 TKI 结合的直接空间位阻、蛋白激酶构象的改变和/或 ATP 结合的变化来产生耐药性[14-16]。
不同于 EGFR 突变型肺癌耐药突变中 T790M 突变占绝大多数的情况,ALK⁺ NSCLC 中导致耐药突变的 ALK 突变类型极为广泛,如 L1196M、G1202R、D1203N 等等[14]。
ALK 非依赖性耐药
约 50% 的第二代 ALK-TKI 耐药可以被归类为 ALK 非依赖性耐药,赋予 ALK TKI 耐药性的不同脱靶机制可能在不同患者之间发生,这使得 ALK 非依赖性耐药难以克服[17,18]。
ALK 非依赖性耐药的一个重要类别是旁路信号的激活,这是由基因改变、蛋白质表达变化和/或自分泌反馈信号的激活或失调引起的。在 ALK TKI 耐药肿瘤中已经描述了多个旁路轨道,包括受体酪氨酸激酶(RTK)MET、EGFR等的激活以及下游信号因子 MAP2K1、STAT3等的改变[19-23]。
此外,肿瘤可转化为不同的组织学亚型,从而导致耐药性[24]。尽管几乎所有新诊断的 ALK⁺ NSCLC 病例都是腺癌,但在接受各代 ALK TKI 治疗后的 ALK⁺ 肺癌患者中已发现小细胞肺癌转化[25-28]。

ALK-TKI 耐药的应对策略

ALK-TKI 序贯治疗
临床实践中不乏先使用一代 TKI,再转换至二代 TKI 的做法,但这种序贯治疗可能增加复合耐药突变的发生率。
以 ALK 为中心的替代方法
针对 ALK 突变的其他方法,例如变构抑制、共价抑制和蛋白降解靶向嵌合体(PROTAC)等,不过相关探索大多还处在临床前阶段,使用价值有待验证。
针对 ALK 非依赖性耐药的联合治疗
虽然 ALK-TKI 耐药相关的很多旁路耐药机制都已有针对性靶向药物可用,但 ALK-TKI 与其它靶向药物联合治疗的临床研究,疗效数据普遍不如人意,一大原因可能是联合用药的副作用较大,限制了用药剂量,另一原因可能是联合治疗会加速其它耐药机制的出现。
基于免疫机制的治疗
ALK 阳性 NSCLC 是著名的冷肿瘤,现有的免疫检查点抑制剂(ICI)也缺乏与 ALK-TKI 的协同增效,不过可以考虑将 ALK 作为个体化肿瘤疫苗的靶标。
肺癌黄金靶点ALK靶向治疗的耐药问题


参考文献
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