Proposal for a synthetic lethality therapy using the paralog dependence of cancer cells-response
Proposal for a synthetic lethality therapy using the paralog dependence of cancer cells-response
复制标题
利用癌细胞反应的旁系同源依赖性的合成致死疗法的提案
DOI：
10.1158/0008-5472.can-14-0674
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发表时间：
2014
期刊：
影响因子：
11.2
通讯作者：
Kohno T
中科院分区：
文献类型：
--
作者：
Oike T;Ogiwara H;Nakano T;Kohno T
我们感谢Thompson博士和他的同事们对我们的文章（1）提出的有见地的评论。我们现在根据他们的评论重新评估了我们的发现。最近，两项研究试图使用与我们使用的相同（和其他）癌细胞系来鉴定BRG 1的合成致死伴侣（2，3）;他们的结论与我们自己的一致。霍夫曼及其同事（2）使用了一个针对262个表观遗传调节因子的深度覆盖设计shRNA（DECODER）文库，以检查基因消融对58个癌细胞系生长的影响。他们发现BRM对于BRG 1中携带功能缺失突变的癌细胞的生长至关重要。Wilson及其同事（3）使用全基因组shRNA筛选11，194个基因，比较了8个携带BRG 1失活突变的癌细胞系和144个没有这些突变的癌细胞系的易感性，发现BRM是BRG 1突变癌细胞中最特异的必需基因。总之，这些研究的结果强烈支持我们的发现，即BRG 1缺陷型癌细胞对BRM耗竭敏感。关于BRG 1或BRM在缺陷细胞系中的恢复以及BRG 1和/或BRM等位基因的敲除的数据强烈表明BRG 1和BRM基因具有肿瘤抑制活性;因此，设计用于抑制BRM功能的疗法乍一看似乎是矛盾的。然而，通过BRG 1缺陷发展的癌细胞可能反过来获得了需要BRM作为基本生存因子的特定细胞环境（我们认为这可能对应于Thompson及其同事提到的“细胞类型和环境条件”之一）。事实上，最近的一项研究表明，BRM是BRG 1缺陷癌细胞中完整SWI/SNF复合物组装所必需的（3）。因此，我们认为我们的结果（以及其他作者的结果;参考文献。1-3)这表明BRG 1缺陷型癌细胞具有特定的脆弱性，这在很大程度上取决于BRG 1蛋白，BRM，我们不否认BRG 1和BRM的肿瘤抑制性质。在ARID 1A/BAF 250 A缺陷型癌细胞中也观察到了类似的脆弱性（这在很大程度上取决于其paratoms，ARID 1B/BAF 250 B;参考文献4），支持基于旁系同源依赖的方法对具有遗传缺陷的癌细胞的合成致死性治疗的适用性。Reisman及其同事（5，6）鉴定了缺乏BRG 1和BRM表达的原发性肺肿瘤的子集。这些肿瘤细胞增殖独立于BRM;因此，致癌过程和染色质重塑机制被认为与仅缺乏BRG 1的肿瘤细胞不同。因此，基于逆转表观遗传学沉默基因（7）或引入microRNA（如Thompson及其同事提出的）的治疗策略将适用于此类肿瘤（预后不良;参考文献5），因为基于BRM耗竭的治疗无效。我们同意，原发性肿瘤中BRG 1和BRM的表观遗传沉默是一个重要的途径，应该追求，因为它是原发性肿瘤中BRG 1/BRM缺陷的主要模式。我们发现，肺癌细胞系II-18，其携带野生型BRG 1基因，但缺乏BRG 1蛋白的表达，易受BRM耗竭的影响（1）。因此，靶向BRM的疗法也可能对携带表观遗传沉默的BRG 1的癌细胞有效。然而，应该检查更多的癌细胞系以得出确切的结论。
We thank Dr. Thompson and colleagues for their insightful comments about our article (1). We have now reevaluated our finding based on their comments. Recently, two studies sought to identify synthetic lethal partners for BRG1 using the same (and other) cancer cell lines as used by us (2, 3); their conclusions were in agreement with our own. Hoffman and colleagues (2) used a deepcoverage design shRNA (DECODER) library targeting 262 epigenetic regulators to examine the effect of gene ablation on the growth of 58 cancer cell lines. They found that BRM is essential for the growth of cancer cells harboring loss-offunction mutations in BRG1. Wilson and colleagues (3) used genome-wide shRNA screening of 11,194 genes to compare the susceptibility of eight cancer cell lines harboring inactivating mutations in BRG1 and 144 cancer cell lines without these mutations with gene ablation and found that BRM was the most specifically essential gene in BRG1-mutant cancer cells. Taken together, the results of these studies strongly support our finding that BRG1-deficient cancer cells are susceptible to BRM depletion. Data about the restoration of BRG1 or BRM in deficient cell lines and the knockout of BRG1 and/or BRM alleles strongly indicate that BRG1 and BRM genes have tumorsuppressive activity; thus, a therapy designed to suppress BRM function appears paradoxical at first glance. However, cancer cells that developed through a BRG1 deficiency might, in turn, have acquired a specific cellular context that needs BRM as an essential survival factor (we believe that this may correspond to one of the" cell type and environmental conditions" mentioned by Thompson and colleagues). Indeed, a recent study shows that BRM is necessary for the assembly of intact SWI/SNF complexes in BRG1-deficient cancer cells (3). Therefore, we believe that our results (and those of other authors; refs. 1–3) indicate that BRG1-deficient cancer cells harbor a specific vulnerability, which largely depends on the BRG1 paralog, BRM, and we do not deny the tumor-suppressive nature of BRG1 and BRM. A similar vulnerability is also observed in ARID1A/BAF250A-deficient cancer cells (which largely depends on its paralog, ARID1B/BAF250B; ref. 4), supporting the applicability of a paralog-dependence-based approach to synthetic lethality therapy for cancer cells with a genetic deficiency.Reisman and colleagues (5, 6) identified a subset of primary lung tumors that lack expression of both BRG1 and BRM. These tumor cells proliferated independent of BRM; thus, the carcinogenic processes and the chromatin remodeling machinery are thought to be different from those in tumor cells lacking only BRG1. Therefore, therapeutic strategies based on reversing epigenetically silenced genes (7) or the introduction of microRNAs (as proposed by Thompson and colleagues) will be applicable to such tumors (which have a poor prognosis; ref. 5) because therapies based on BRM depletion are not effective. We agree that epigenetic silencing of BRG1 and BRM in primary tumors is an important avenue that should be pursued because it is a major mode of BRG1/BRM deficiency in primary tumors. We showed that a lung cancer cell line, II-18, which harbors the wild-type BRG1 gene but lacks expression of the BRG1 protein, is susceptible to BRM depletion (1). Therefore, therapies that target BRM might also be effective against cancer cells harboring epigenetically silenced BRG1. However, more cancer cell lines should be examined to draw firm conclusions.