PO.ET09.06 · 实验与分子治疗
靶向 AhR 抑制 EGFR 突变型肺癌中 amivantamab-lazertinib 诱导的耐药持留细胞的产生
Targeting AhR suppresses the generation of amivantamab-lazertinib-induced drug-tolerant persisters in EGFR-mutant lung cancer
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摘要 Abstract
中文摘要
引言:2024 年,美国 FDA 基于 MARIPOSA 试验批准了一线 amivantamab-lazertinib 疗法,该试验显示其总生存期优于奥希替尼(osimertinib)。然而,对这种双靶点疗法的耐药机制仍知之甚少。通过对患者来源和临床前模型的多组学分析,我们将芳香烃受体(AhR)鉴定为克服 amivantamab-lazertinib 耐药的潜在靶点。
方法:将一名初治(treatment-naïve)EGFR 19 外显子缺失患者的新鲜肿瘤样本移植到无胸腺裸鼠中,建立患者来源异种移植(PDX)模型。小鼠接受 amivantamab-lazertinib 治疗 10 天,随后进行单细胞和批量 RNA 测序、全外显子组测序和免疫组化,以评估早期反应。在体外,流式细胞术检测 lazertinib 诱导的 AhR 表达,HepG2 AhR-荧光素酶报告基因检测评估 lazertinib 与 AhR 的结合。计算机对接(SAMSON)评估了结合亲和力。CellTiter-Glo 和集落形成检测测试了 amivantamab、lazertinib 和 DA-4505(一种在研 AhR 拮抗剂)的联合作用。
结果:单细胞 RNA 测序鉴定出 AhR 是 amivantamab-lazertinib 暴露后耐药持留(DTP)细胞中上调最显著的基因之一。对接分析提示 lazertinib 起 AhR 激动剂的作用。FACS 证实该联合方案在多种 NSCLC 细胞系中显著增加了 AhR 表达。加入 DA-4505 增强了对 H1975 和 YU-1185 患者来源细胞的生长抑制,集落检测证实了相加效应。转录组学和磷酸化流式分析表明,Src 信号激活的细胞系对三药联合治疗最为敏感。一项 I 期试验的早期临床数据显示,DA-4505 单药治疗在剂量高达 400 mg 时耐受性良好。
结论:用 DA-4505 靶向 AhR 可增强 amivantamab-lazertinib 的疗效,并可能减轻 EGFR 突变型 NSCLC 中的耐药。正在进行的临床评估将确定其转化潜力。
查看英文原文 English abstract
Introduction: In 2024, the U.S. FDA approved first-line amivantamab-lazertinib based on the MARIPOSA trial, which showed superior overall survival compared with osimertinib. However, mechanisms of resistance to this dual-target therapy remain poorly understood. Using multi-omics analyses of patient-derived and preclinical models, we identified the aryl hydrocarbon receptor (AhR) as a potential target to overcome amivantamab-lazertinib resistance.
Methods: Fresh tumor samples from a treatment-naïve EGFR exon 19 deletion patient were transplanted into athymic nude mice to establish patient-derived xenograft (PDX) models. Mice were treated with amivantamab-lazertinib for 10 days, followed by single-cell and bulk RNA sequencing, whole-exome sequencing, and immunohistochemistry to assess early-phase responses. In vitro, flow cytometry measured lazertinib-induced AhR expression, and HepG2 AhR-luciferase reporter assays evaluated lazertinib-AhR binding. In silico docking (SAMSON) assessed binding affinity. CellTiter-Glo and colony-formation assays tested combinatorial effects of amivantamab, lazertinib, and DA-4505, an investigational AhR antagonist.
Results: Single-cell RNA-seq identified AhR among the most upregulated genes in drug-tolerant persister (DTP) cells after amivantamab-lazertinib exposure. Docking analysis suggested lazertinib acts as an AhR agonist. FACS
confirmed that the combination markedly increased AhR expression across NSCLC cell lines. Adding DA-4505 enhanced growth inhibition in H1975 and YU-1185 patient-derived cells, with colony assays confirming additive effects. Transcriptomic and phospho-flow analyses indicated that cell lines with activated Src signaling were most sensitive to triple-drug treatment. Early clinical data from a phase I trial showed DA-4505 monotherapy was well tolerated up to 400 mg.
Conclusion: Targeting AhR with DA-4505 augments the efficacy of amivantamab-lazertinib and may mitigate resistance in EGFR-mutant NSCLC. Ongoing clinical evaluation will determine its translational potential.
利益披露 Disclosure
J. Shim, None.