Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Bioinformatics Department, School of Life Sciences and Technology, Tongji University, Shanghai, China.
Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Nat Commun. 2021 Feb 24;12(1):1275. doi: 10.1038/s41467-021-21544-2.
Synthetic lethality is emerging as an important cancer therapeutic paradigm, while the comprehensive selective treatment opportunities for various tumors have not yet been explored. We develop the Synthetic Lethality Knowledge Graph (SLKG), presenting the tumor therapy landscape of synthetic lethality (SL) and synthetic dosage lethality (SDL). SLKG integrates the large-scale entity of different tumors, drugs and drug targets by exploring a comprehensive set of SL and SDL pairs. The overall therapy landscape is prioritized to identify the best repurposable drug candidates and drug combinations with literature supports, in vitro pharmacologic evidence or clinical trial records. Finally, cladribine, an FDA-approved multiple sclerosis treatment drug, is selected and identified as a repurposable drug for treating melanoma with CDKN2A mutation by in vitro validation, serving as a demonstrating SLKG utility example for novel tumor therapy discovery. Collectively, SLKG forms the computational basis to uncover cancer-specific susceptibilities and therapy strategies based on the principle of synthetic lethality.
合成致死性正在成为一种重要的癌症治疗范例，而各种肿瘤的全面选择性治疗机会尚未得到探索。我们开发了合成致死性知识图谱 (SLKG)，呈现了合成致死性 (SL) 和合成剂量致死性 (SDL) 的肿瘤治疗全景。SLKG 通过探索一整套 SL 和 SDL 对，整合了不同肿瘤、药物和药物靶点的大规模实体。根据文献支持、体外药理证据或临床试验记录，对整体治疗全景进行优先级排序，以确定最佳可再利用的药物候选物和药物组合。最后，选择并确定已获 FDA 批准用于多发性硬化症治疗的克拉屈滨作为治疗 CDKN2A 突变黑色素瘤的可再利用药物，通过体外验证为新的肿瘤治疗发现提供了 SLKG 实用示例。总之，SLKG 为基于合成致死性原则发现癌症特异性易感性和治疗策略提供了计算基础。
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