Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China.
Clinical Research Center (CRC), Medical Pathology Center (MPC), Cancer Early Detection and Treatment Center (CEDTC), Chongqing University Three Gorges Hospital, Chongqing University, Wanzhou, Chongqing, China.
Cancer Lett. 2024 Jul 10;594:216991. doi: 10.1016/j.canlet.2024.216991. Epub 2024 May 24.
Genetic interactions (GIs) refer to two altered genes having a combined effect that is not seen individually. They play a crucial role in influencing drug efficacy. We utilized CGIdb 2.0 (http://www.medsysbio.org/CGIdb2/), an updated database of comprehensively published GIs information, encompassing synthetic lethality (SL), synthetic viability (SV), and chemical-genetic interactions. CGIdb 2.0 elucidates GIs relationships between or within protein complex models by integrating protein-protein physical interactions. Additionally, we introduced GENIUS (GENetic Interactions mediated drUg Signature) to leverage GIs for identifying the response signature of immune checkpoint inhibitors (ICIs). GENIUS identified high MAP4K4 expression as a resistant signature and high HERC4 expression as a sensitive signature for ICIs treatment. Melanoma patients with high expression of MAP4K4 were associated with decreased efficacy and poorer survival following ICIs treatment. Conversely, overexpression of HERC4 in melanoma patients correlated with a positive response to ICIs. Notably, HERC4 enhances sensitivity to immunotherapy by facilitating antigen presentation. Analyses of immune cell infiltration and single-cell data revealed that B cells expressing MAP4K4 may contribute to resistance to ICIs in melanoma. Overall, CGIdb 2.0, provides integrated GIs data, thus serving as a crucial tool for exploring drug effects.
遗传相互作用（Genetic interactions，GIs）是指两个改变的基因共同作用产生的效果，而不是各自独立产生的效果。它们在影响药物疗效方面起着至关重要的作用。我们利用了 CGIdb 2.0（http://www.medsysbio.org/CGIdb2/），这是一个经过更新的综合发表遗传相互作用信息数据库，包括合成致死性（Synthetic lethality，SL）、合成活力性（Synthetic viability，SV）和化学遗传相互作用。CGIdb 2.0 通过整合蛋白质-蛋白质物理相互作用来阐明蛋白质复合物模型之间或内部的遗传相互作用关系。此外，我们引入了 GENIUS（GENetic Interactions mediated drUg Signature），利用遗传相互作用来识别免疫检查点抑制剂（Immune Checkpoint Inhibitors，ICIs）的反应特征。GENIUS 确定高表达 MAP4K4 是对 ICI 治疗的耐药特征，而高表达 HERC4 是对 ICI 治疗的敏感特征。高表达 MAP4K4 的黑色素瘤患者在接受 ICI 治疗后疗效降低，生存状况恶化。相反，HERC4 在黑色素瘤患者中的过表达与对 ICI 的积极反应相关。值得注意的是，HERC4 通过促进抗原呈递来增强对免疫治疗的敏感性。免疫细胞浸润和单细胞数据分析表明，表达 MAP4K4 的 B 细胞可能导致黑色素瘤对 ICI 的耐药。总的来说，CGIdb 2.0 提供了综合的遗传相互作用数据，因此是探索药物作用的重要工具。
