Targeting the MAPK signaling pathway has transformed the treatment of metastatic melanoma. CRISPR‐Cas9 genetic screens provide a genome‐wide approach to uncover novel genetic dependencies that might serve as therapeutic targets. Here, we analyzed recently reported CRISPR‐Cas9 screens comparing data from 28 melanoma cell lines and 313 cell lines of other tumor types in order to identify fitness genes related to melanoma. We found an average of 1,494 fitness genes in each melanoma cell line. We identified 33 genes, inactivation of which specifically reduced the fitness of melanoma. This set of tumor type‐specific genes includes established melanoma fitness genes as well as many genes that have not previously been associated with melanoma growth. Several genes encode proteins that can be targeted using available inhibitors. We verified that genetic inactivation of DUSP4 and PPP2R2A reduces the proliferation of melanoma cells. DUSP4 encodes an inhibitor of ERK, suggesting that further activation of MAPK signaling activity through its loss is selectively deleterious to melanoma cells. Collectively, these data present a resource of genetic dependencies in melanoma that may be explored as potential therapeutic targets.

中文翻译：

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CRISPR-Cas9 筛选分析确定了黑色素瘤的遗传依赖性。

以 MAPK 信号通路为靶点已经改变了转移性黑色素瘤的治疗方法。CRISPR-Cas9 遗传筛选提供了一种全基因组方法来发现可能作为治疗靶点的新遗传依赖性。在这里，我们分析了最近报道的 CRISPR-Cas9 筛选，比较了 28 个黑色素瘤细胞系和 313 个其他肿瘤类型细胞系的数据，以便识别与黑色素瘤相关的适应性基因。我们在每个黑色素瘤细胞系中平均发现 1,494 个适应基因。我们鉴定了 33 个基因，这些基因的失活会显着降低黑色素瘤的适应性。这组肿瘤类型特异性基因包括已确定的黑色素瘤适应基因以及许多以前与黑色素瘤生长无关的基因。一些基因编码可以使用现有抑制剂靶向的蛋白质。我们验证了DUSP4和PPP2R2A的基因失活可减少黑色素瘤细胞的增殖。DUSP4编码 ERK 抑制剂，表明通过其缺失进一步激活 MAPK 信号活性选择性地对黑色素瘤细胞有害。总的来说，这些数据提供了黑色素瘤遗传依赖性的资源，可以将其作为潜在的治疗靶点进行探索。