Loss of functional BAP1 augments sensitivity to TRAIL in cancer cells.
Loss of functional BAP1 augments sensitivity to TRAIL in cancer cells.
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功能性BAP1的丧失增强了对癌细胞中触发的敏感性。
DOI：
10.7554/elife.30224
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发表时间：
2018-01-18
期刊：
影响因子：
7.7
通讯作者：
Janes SM
中科院分区：
文献类型：
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作者：
Kolluri KK;Alifrangis C;Kumar N;Ishii Y;Price S;Michaut M;Williams S;Barthorpe S;Lightfoot H;Busacca S;Sharkey A;Yuan Z;Sage EK;Vallath S;Le Quesne J;Tice DA;Alrifai D;von Karstedt S;Montinaro A;Guppy N;Waller DA;Nakas A;Good R;Holmes A;Walczak H;Fennell DA;Garnett M;Iorio F;Wessels L;McDermott U;Janes SM
恶性间皮瘤（MM）对全身性细胞毒性化疗反应不佳，且总是致命的。在此我们描述了对15种外显子组测序的MM细胞系中的94种药物的筛选，以及发现了一个由核去泛素化酶BRCA相关蛋白 - 1（BAP1）功能缺失所定义的亚群，该亚群对TRAIL（肿瘤坏死因子相关凋亡诱导配体）表现出更高的敏感性。这种关联在人类早期传代的MM培养物、小鼠异种移植物和人类肿瘤外植体中均被观察到。我们证明BAP1去泛素化酶活性及其与ASXL1结合形成多梳抑制性去泛素化酶复合物（PR - DUB）影响TRAIL敏感性，暗示转录调节是一种潜在机制。死亡受体激动剂是耐受性良好的抗癌药物，在没有靶向生物标志物的试验中显示出有限的治疗益处。我们确定BAP1功能缺失突变（在MM中常见）可作为TRAIL敏感性的一种潜在基因组分层工具，具有直接且可操作的治疗意义。
两名患有相同疾病并接受相同治疗的患者可能会有不同的反应。这种差异通常源于每个患者遗传密码的不同。基因编码蛋白质，而蛋白质是大多数药物的作用靶点，因此决定了患者对治疗的反应。
21世纪的一项重大进展是医生认识到患者对相同治疗可能有不同反应，并且现在试图预测哪些患者对哪种药物反应最佳——这种方法被称为个性化医疗。癌症治疗一直处于个性化医疗的前沿，因为不同的癌症是由不同基因的突变引起的。通过分析癌症中存在哪些突变，医生可以预测哪种药物（或药物组合）将最有效。这种方法已在几种癌症中成功应用，包括乳腺癌和肺癌，使得更少的患者接受无效治疗以及避免相关的副作用和费用。
间皮瘤是一种与接触矿物质石棉有关的肺内膜癌症。不幸的是，目前间皮瘤的治疗选择有限且效果不佳。目前没有个性化治疗方法在使用，迫切需要新的治疗方法。
科卢里、阿里弗兰吉斯、库马尔、石井等人着手确定间皮瘤中常见的任何突变是否会影响癌症对94种正在使用或研发中的抗癌药物的反应。在实验室中，编码一种称为BRCA相关蛋白 - 1（简称BAP1）的蛋白质的基因发生突变的间皮瘤细胞被一种称为肿瘤坏死因子相关凋亡诱导配体（TRAIL）的药物更有效地杀死。在将间皮瘤细胞肿瘤移植到小鼠的实验中以及从患者身上获取的间皮瘤肿瘤碎片中也看到了相同的联系。当科卢里等人研究为什么这些肿瘤可能被TRAIL更有效地杀死时，他们发现BAP1基因的突变导致传递TRAIL药物靶向受体信号的蛋白质水平发生变化。
这些发现可能有一天会导致一种治疗间皮瘤患者的新方法。但首先，下一步将是对间皮瘤患者进行TRAIL的临床试验，并评估那些肿瘤中BAP1基因发生突变的患者是否确实反应更好。如果事实证明如此，这将为患有这种疾病的患者带来一种新的个性化治疗选择。
Malignant mesothelioma (MM) is poorly responsive to systemic cytotoxic chemotherapy and invariably fatal. Here we describe a screen of 94 drugs in 15 exome-sequenced MM lines and the discovery of a subset defined by loss of function of the nuclear deubiquitinase BRCA associated protein-1 (BAP1) that demonstrate heightened sensitivity to TRAIL (tumour necrosis factor-related apoptosis-inducing ligand). This association is observed across human early passage MM cultures, mouse xenografts and human tumour explants. We demonstrate that BAP1 deubiquitinase activity and its association with ASXL1 to form the Polycomb repressive deubiquitinase complex (PR-DUB) impacts TRAIL sensitivity implicating transcriptional modulation as an underlying mechanism. Death receptor agonists are well-tolerated anti-cancer agents demonstrating limited therapeutic benefit in trials without a targeting biomarker. We identify BAP1 loss-of-function mutations, which are frequent in MM, as a potential genomic stratification tool for TRAIL sensitivity with immediate and actionable therapeutic implications. Two patients with the same disease who receive the same treatment may respond in different ways. This variation often arises from differences in each patient’s genetic code. Genes encode proteins, and proteins are the targets of most medical drugs and thus determine the patient’s response to treatment. A major advance in the 21st century is that doctors recognise that patients can respond differently to the same treatment and now try to predict which patients will respond best to which drug – an approach known as personalised medicine. Cancer treatment has been at the forefront of personalised medicine because mutations in different genes underlie each different cancer. By analysing which mutations are present in a cancer, doctors can thus predict which drug (or combination of drugs) will be most effective. This approach has been used successfully in several cancers, including breast and lung cancer, leading to fewer patients being exposed to ineffective treatments and their associated side effects and costs. Mesothelioma is a cancer of the lining of the lung that is associated with exposure to the mineral asbestos. Current treatment options for mesothelioma are unfortunately limited and not very effective. No personalised treatments are currently in use and new treatment approaches are desperately needed. Kolluri, Alifrangis, Kumar, Ishii et al. set out to determine if any of the mutations commonly seen in mesothelioma affected how the cancer would respond to 94 anticancer drugs that are either in use or in development. In the laboratory, mesothelioma cells that have mutations in the gene that codes for a protein known as BRCA associated protein-1 (or BAP1 for short) were killed much more effectively by a drug known as TNF-related apoptosis-inducing ligand (TRAIL). The same link was seen in experiments with tumours of mesothelioma cells that had been transplanted into mice, and for fragments of mesothelioma tumours taken from patients. When Kolluri et al. studied why these tumours might be killed more effectively with TRAIL, they found that mutations in the gene for BAP1 result in a change in the levels of proteins that transmit the signal from the receptors targeted by the TRAIL drug. These findings may one day result in a new approach to treating patients with mesothelioma. But first, the next step would be to conduct a clinical trial of TRAIL in patients with mesothelioma and assess if those with tumours that have mutations in the gene for BAP1 do indeed respond better. If this proves to be the case, this would result in a new personalised treatment option for patients that suffer from this disease.