Small-cell lung cancer (SCLC) is the most lethal type of lung cancer. Specifically, MYC-driven non-neuroendocrine SCLC is particularly resistant to standard therapies. Lurbinectedin was recently approved for the treatment of relapsed SCLC, but combinatorial approaches are needed to increase the depth and duration of responses to lurbinectedin. Using high-throughput screens, we found inhibitors of ataxia telangiectasia mutated and rad3 related (ATR) as the most effective agents for augmenting lurbinectedin efficacy. First-in-class ATR inhibitor berzosertib synergized with lurbinectedin in multiple SCLC cell lines, organoid, and in vivo models. Mechanistically, ATR inhibition abrogated S-phase arrest induced by lurbinectedin and forced cell cycle progression causing mitotic catastrophe and cell death. High CDKN1A/p21 expression was associated with decreased synergy due to G1 arrest, while increased levels of ERCC5/XPG were predictive of increased combination efficacy. Importantly, MYC-driven non-neuroendocrine tumors which are resistant to first-line therapies show reduced CDKN1A/p21 expression and increased ERCC5/XPG indicating they are primed for response to lurbinectedin–berzosertib combination. The combination is being assessed in a clinical trial NCT04802174.

中文翻译：

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ATR 抑制增强了 lurbinectedin 在小细胞肺癌中的疗效

小细胞肺癌（SCLC）是最致命的肺癌类型。具体来说，MYC 驱动的非神经内分泌 SCLC 对标准疗法特别耐药。Lurbinectedin 最近被批准用于治疗复发性 SCLC，但需要组合方法来增加 lurbinectedin 反应的深度和持续时间。通过高通量筛选，我们发现共济失调毛细血管扩张突变和 rad3 相关 (ATR) 抑制剂是增强 lurbinectedin 功效的最有效药物。一流的 ATR 抑制剂 berzosertib 在多种 SCLC 细胞系、类器官和体内模型中与 lurbinectedin 具有协同作用。从机制上讲，ATR 抑制消除了 lurbinectedin 诱导的 S 期停滞，并强制细胞周期进展，导致有丝分裂灾难和细胞死亡。CDKN1A /p21高表达与 G1 期停滞导致的协同作用降低相关，而ERCC5 /XPG 水平升高则预示着联合疗效的提高。重要的是，对一线疗法耐药的 MYC 驱动的非神经内分泌肿瘤表现出CDKN1A /p21 表达减少和ERCC5 /XPG 增加，表明它们已准备好对 lurbinectedin-berzosertib 组合产生反应。该组合正在临床试验 NCT04802174 中进行评估。