美国哈佛医学院William R. Sellers研究团队通过旁系物敲除分析确定DUSP4和DUSP6是MAPK途径驱动的癌症中的双基因依赖性。这一研究成果于2021年12月2日在线发表在国际学术期刊《自然—遗传学》上。

研究人员表示，尽管单基因扰动筛选发现了一些新的靶标，但经常改变的驱动因素所特有的脆弱性还没有被发现。一个重要的问题是功能冗余基因之间的补偿关系是否掩盖了单基因扰动研究中的潜在治疗靶标。

为了确定二基因依赖关系，研究人员开发了一个CRISPR旁系物靶向库，来研究了破坏3,284个基因、5,065个旁系物对和815个旁系物家族的生存能力影响。研究人员发现，DUSP4和DUSP6的双重失活通过MAPK信号的过度激活选择性地损害了NRAS和BRAF突变体细胞的生长。此外，对MAPK途径治疗剂有抵抗力的细胞对DUSP4和DUSP6扰动变得交叉敏感，因此，对抑制剂的抵抗机制加强了这种脆弱的机制。总之，多基因扰动技术揭示了以前没有认识到的基因弱点，这些弱点可能被用作癌症的新治疗靶标。

附：英文原文

Title: Paralog knockout profiling identifies DUSP4 and DUSP6 as a digenic dependence in MAPK pathway-driven cancers

Author: Ito, Takahiro, Young, Michael J., Li, Ruitong, Jain, Sidharth, Wernitznig, Andreas, Krill-Burger, John M., Lemke, Christopher T., Monducci, Davide, Rodriguez, Diego J., Chang, Liang, Dutta, Sanjukta, Pal, Debjani, Paolella, Brenton R., Rothberg, Michael V., Root, David E., Johannessen, Cory M., Parida, Laxmi, Getz, Gad, Vazquez, Francisca, Doench, John G., Zamanighomi, Mahdi, Sellers, William R.

Issue&Volume: 2021-12-02

Abstract: 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.

DOI: 10.1038/s41588-021-00967-z

Source: https://www.nature.com/articles/s41588-021-00967-z