BRCA1/MAD2L1 Deficiency Disrupts the Spindle Assembly Checkpoint to Confer Vinorelbine Resistance in Mesothelioma
BRCA1/MAD2L1 Deficiency Disrupts the Spindle Assembly Checkpoint to Confer Vinorelbine Resistance in Mesothelioma
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DOI：
10.1158/1535-7163.mct-20-0363
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发表时间：
2021-02-01
影响因子：
5.7
通讯作者：
Fennell, Dean A.
中科院分区：
文献类型：
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作者：
Busacca, Sara;O'Regan, Laura;Fennell, Dean A.
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 启动细胞凋亡。然而，这种调节的机制和临床意义尚未被探索。在这里，我们发现 BRCA1 沉默消除了长春瑞滨诱导的细胞周期停滞、BUBR1 募集至动粒和细胞凋亡。 BRCA1 沉默导致 MAD2L1 在 mRNA 和蛋白质水平上共缺失，与其作为 BRCA1 转录靶标的地位一致。 MAD2L1 的沉默使 BRCA1 具有表型，并足以赋予对长春瑞滨的耐药性。这在选择对长春瑞滨具有抗性的细胞系中得到了重现，这些细胞系获得了 BRCA1 和 MAD2L1 表达的丧失。在 20 个原发性肿瘤外植体中离体长春瑞滨后，BRCA1/MAD2L1 阳性外植体中的细胞凋亡反应率为 59%，而 BRCA1/MAD2L1 阴性外植体中的细胞凋亡反应率为 0%。在 48 名患者中，BRCA1 和/或 MAD2L1 表达缺失并不具有预后意义；然而，在接受长春瑞滨治疗的一组患者中，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 缺失是间皮瘤长春瑞滨耐药的推定预测标志物，值得前瞻性临床评估。
Mesothelioma is a universally lethal cancer lacking effective therapy. The spindle poison vinorelbine exhibits clinical activity in the 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 codepletion 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 tumor 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 vs. 36.7 months, P = 0.03). Our data implicate BRCA1/MAD2L1 loss as a putative predictive marker of resistance to vinorelbine in mesothelioma and warrant prospective clinical evaluation.