【原】Nature genetics: 多基因编辑技术揭示了以前未被认识到的基因脆弱性，可能被用作癌症的新治疗靶点。

虽然单基因干扰筛选已经揭示了一些新的目标，但经常改变司机的特定弱点还没有被发现。一个重要的问题是，在单基因干扰研究中，功能冗余基因之间的代偿关系是否掩盖了潜在的治疗靶点。为了确定基因依赖关系，我们开发了一个CRISPR旁系靶基因筛选库，以研究干扰3284个基因、5065对类似基因对和815个类似基因家族的生存能力影响。我们发现DUSP4和DUSP6的双重失活通过过度激活MAPK信号通路，选择性地损害NRAS和BRAF突变细胞的生长。此外，对MAPK通路疗法产生抗性的细胞对DUSP4和DUSP6干扰产生交叉敏感，这样，对抑制剂的抗性机制加强了这种脆弱性机制。总之，多基因干扰技术揭示了以前未被认识到的基因脆弱性，可能被用作癌症的新治疗靶点。

Although single-gene perturbation screens have revealed a number of new targets, vulnerabilities specific to frequently altered drivers have not been uncovered. An important question is whether the compensatory relationship between functionally redundant genes masks potential therapeutic targets in single-gene perturbation studies. To identify digenic dependencies, we developed a CRISPR paralog targeting library to investigate the viability effects of disrupting 3,284 genes, 5,065 paralog pairs and 815 paralog families. We identified that dual inactivation of DUSP4 and DUSP6 selectively impairs growth in NRAS and BRAF mutant cells through the hyperactivation of MAPK signaling. Furthermore, cells resistant to MAPK pathway therapeutics become cross-sensitized to DUSP4 and DUSP6 perturbations such that the mechanisms of resistance to the inhibitors reinforce this mechanism of vulnerability. Together, multigene perturbation technologies unveil previously unrecognized digenic vulnerabilities that may be leveraged as new therapeutic targets in cancer.

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