In non-small cell lung cancer (NSCLC) treatment, radiotherapy responses are not durable and toxicity limits therapy. We find that AM-101, a synthetic benzodiazepine activator of GABA(A) receptor, impairs the viability and clonogenicity of both primary and brain-metastatic NSCLC cells. Employing a human-relevant ex vivo ‘chip’, AM-101 is as efficacious as docetaxel, a chemotherapeutic used with radiotherapy for advanced-stage NSCLC. In vivo, AM-101 potentiates radiation, including conferring a significant survival benefit to mice bearing NSCLC intracranial tumors generated using a patient-derived metastatic line. GABA(A) receptor activation stimulates a selective-autophagic response via the multimerization of GABA(A) receptor-associated protein, GABARAP, the stabilization of mitochondrial receptor Nix, and the utilization of ubiquitin-binding protein p62. A high-affinity peptide disrupting Nix binding to GABARAP inhibits AM-101 cytotoxicity. This supports a model of GABA(A) receptor activation driving a GABARAP–Nix multimerization axis that triggers autophagy. In patients receiving radiotherapy, GABA(A) receptor activation may improve tumor control while allowing radiation dose de-intensification to reduce toxicity.
在非小细胞肺癌（NSCLC）治疗中，放疗反应难以持久且毒性作用限制了治疗效果。本研究发现，AM-101作为一种人工合成的γ-氨基丁酸A型受体苯二氮䓬类激活剂，能够显著抑制原发性和脑转移性NSCLC细胞的活力与克隆形成能力。通过人源化离体“芯片”模型验证，AM-101与晚期NSCLC放化疗联合用药多西他赛具有同等疗效。在体内实验中，AM-101可增强放疗效果，对携带患者来源转移细胞系构建的颅内NSCLC肿瘤模型小鼠产生显著的生存获益。机制研究表明，γ-氨基丁酸A型受体激活通过促进其关联蛋白GABARAP的多聚化、稳定线粒体受体Nix并利用泛素结合蛋白p62，进而引发选择性自噬反应。采用高亲和力多肽阻断Nix与GABARAP的结合可抑制AM-101的细胞毒性作用，这证实了γ-氨基丁酸A型受体激活通过驱动GABARAP-Nix多聚化轴触发自噬的机制模型。对于接受放疗的患者，γ-氨基丁酸A型受体激活在改善肿瘤控制的同时，有望通过降低放疗剂量强度来减少治疗毒性。
肿瘤(癌症)患者之家