通过广泛的组合泛癌CRISPR筛选定义的合成致死基因对简编。

A compendium of synthetic lethal gene pairs defined by extensive combinatorial pan-cancer CRISPR screening.

作者信息

Harle Victoria, Offord Victoria, Gökbağ Birkan, Fotopoulos Lazaros, Williams Thomas, Alexander Diana, Mehta Ishan, Thompson Nicola A, Olvera-León Rebeca, Peidli Stefan, Iyer Vivek, Gonçalves Emanuel, Kebabci Narod, De Kegel Barbara, van de Haar Joris, Li Lang, Ryan Colm J, Adams David J

机构信息

Wellcome Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

Department of Biomedical Informatics, The Ohio State University, College of Medicine, Columbus, OH, 43210, USA.

出版信息

Genome Biol. 2025 Sep 18;26(1):284. doi: 10.1186/s13059-025-03737-w.

DOI:10.1186/s13059-025-03737-w

PMID:40968372

Abstract

BACKGROUND

Synthetic lethal interactions are attractive therapeutic candidates as they enable selective targeting of cancer cells in which somatic alterations have disrupted one member of a synthetic lethal gene pair while leaving normal tissues untouched, thus minimising off-target toxicity. Despite this potential, the number of well-established and validated synthetic lethal gene pairs is modest.

RESULTS

We generate a dual-guide CRISPR/Cas9 Library and analyse 472 predicted synthetic lethal pairs in 27 cancer cell Lines from melanoma, pancreatic and lung cancer Lineages. We report a robust collection of 117 genetic interactions within and across cancer types and explore their candidacy as therapeutic targets. We show that SLC25A28 is an attractive target since its synthetic lethal paralog partner SLC25A37 is homozygously deleted pan-cancer. We generate knockout mice for Slc25a28 revealing that, except for cataracts in some mice, these animals are normal; suggesting inhibition of SLC25A28 is unlikely to be associated with profound toxicity.

CONCLUSIONS

We provide and validate an extensive collection of synthetic lethal interactions across cancer types.

摘要

背景

合成致死相互作用是有吸引力的治疗候选对象，因为它们能够选择性地靶向癌细胞，在这些癌细胞中，体细胞改变破坏了合成致死基因对中的一个成员，而正常组织不受影响，从而将脱靶毒性降至最低。尽管有这种潜力，但已确立并经过验证的合成致死基因对数量并不多。

结果

我们构建了一个双向导CRISPR/Cas9文库，并分析了来自黑色素瘤、胰腺癌和肺癌谱系的27种癌细胞系中的472对预测的合成致死基因对。我们报告了一组强大的、跨癌症类型的117种遗传相互作用，并探讨了它们作为治疗靶点的可能性。我们表明，SLC25A28是一个有吸引力的靶点，因为其合成致死旁系同源伴侣SLC25A37在全癌中均为纯合缺失。我们构建了Slc25a28基因敲除小鼠，发现除了一些小鼠出现白内障外，这些动物都是正常的；这表明抑制SLC25A28不太可能与严重毒性相关。