Mesothelioma is a universally lethal cancer lacking effective therapy. The spindle poison vinorelbine exhibits clinical activity in relapsed setting, and in preclinical models requires BRCA1 to initiate apoptosis. However, the mechanisms underlying this regulation and the clinical implications have not been explored. Here we show that BRCA1 silencing abrogated vinorelbine-induced cell cycle arrest, recruitment of BUBR1 to kinetochores, and apoptosis. BRCA1 silencing led to co-depletion of MAD2L1 at the mRNA and protein levels consistent with its status as a transcriptional target of BRCA1. Silencing of MAD2L1 phenocopied BRCA1, and was sufficient to confer resistance to vinorelbine. This was recapitulated in cell lines selected for resistance to vinorelbine, which acquired loss of both BRCA1 and MAD2L1 expression. Following ex-vivo vinorelbine in 20 primary tumour explants, apoptotic response rate was 59% in BRCA1/MAD2L1 positive explants compared with 0% in BRCA1/MAD2L1 negative explants. In 48 patients BRCA1 and/or MAD2L1 loss of expression was not prognostic, however in a subset of patients treated with vinorelbine, survival was shorter for patients lacking BRCA1/MAD2L1 expression compared with double positive patients (5.9 versus 36.7 months, p=0.03). Our data implicates BRCA1/MAD2L1 loss as a putative predictive marker of resistance to vinorelbine in mesothelioma, and warrants prospective clinical evaluation.

中文翻译：

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BRCA1/MAD2L1 缺陷会破坏纺锤体组装检查点，从而赋予间皮瘤长春瑞滨抗性

间皮瘤是一种普遍致命的癌症，缺乏有效的治疗方法。纺锤体毒物长春瑞滨在复发环境中表现出临床活性，并且在临床前模型中需要 BRCA1 来启动细胞凋亡。然而，尚未探索该调节的潜在机制和临床意义。在这里我们展示了 BRCA1 沉默废除了长春瑞滨诱导的细胞周期停滞、BUBR1 向动粒的募集和细胞凋亡。BRCA1 沉默导致 MAD2L1 在 mRNA 和蛋白质水平上的共同消耗，与其作为 BRCA1 转录靶标的状态一致。MAD2L1 的沉默表型 BRCA1，足以赋予对长春瑞滨的抗性。这在针对长春瑞滨抗性选择的细胞系中重现，长春瑞滨获得了 BRCA1 和 MAD2L1 表达的丧失。在 20 个原发肿瘤外植体中离体长春瑞滨后，BRCA1/MAD2L1 阳性外植体的凋亡反应率为 59%，而 BRCA1/MAD2L1 阴性外植体的凋亡反应率为 0%。在 48 名患者中，BRCA1 和/或 MAD2L1 的表达缺失不具有预后意义，但是在接受长春瑞滨治疗的一部分患者中，与双阳性患者相比，缺乏 BRCA1/MAD2L1 表达的患者的生存期较短（5.9 个月与 36.7 个月，p=0.03） . 我们的数据表明 BRCA1/MAD2L1 缺失是间皮瘤中长春瑞滨耐药性的推定预测标志物，值得进行前瞻性临床评估。然而，在接受长春瑞滨治疗的一部分患者中，与双阳性患者相比，缺乏 BRCA1/MAD2L1 表达的患者的生存期较短（5.9 个月 vs 36.7 个月，p=0.03）。我们的数据表明 BRCA1/MAD2L1 缺失是间皮瘤中长春瑞滨耐药性的推定预测标志物，值得进行前瞻性临床评估。然而，在接受长春瑞滨治疗的一部分患者中，与双阳性患者相比，缺乏 BRCA1/MAD2L1 表达的患者的生存期较短（5.9 个月 vs 36.7 个月，p=0.03）。我们的数据表明 BRCA1/MAD2L1 缺失是间皮瘤中长春瑞滨耐药性的推定预测标志物，值得进行前瞻性临床评估。