Ngoi Natalie Y L, Gallo David, Torrado Carlos, Nardo Mirella, Durocher Daniel, Yap Timothy A
Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore.
Nat Rev Clin Oncol. 2025 Jan;22(1):46-64. doi: 10.1038/s41571-024-00966-z. Epub 2024 Dec 3.
Synthetic lethality is a genetic phenomenon whereby the simultaneous presence of two different genetic alterations impairs cellular viability. Importantly, targeting synthetic lethal interactions offers potential therapeutic strategies for cancers with alterations in pathways that might otherwise be considered undruggable. High-throughput screening methods based on modern CRISPR-Cas9 technologies have emerged and become crucial for identifying novel synthetic lethal interactions with the potential for translation into biologically rational cancer therapeutic strategies as well as associated predictive biomarkers of response capable of guiding patient selection. Spurred by the clinical success of PARP inhibitors in patients with BRCA-mutant cancers, novel agents targeting multiple synthetic lethal interactions within DNA damage response pathways are in clinical development, and rational strategies targeting synthetic lethal interactions spanning alterations in epigenetic, metabolic and proliferative pathways have also emerged and are in late preclinical and/or early clinical testing. In this Review, we provide a comprehensive overview of established and emerging technologies for synthetic lethal drug discovery and development and discuss promising therapeutic strategies targeting such interactions.
合成致死是一种遗传现象，即两种不同的基因改变同时存在会损害细胞活力。重要的是，针对合成致死相互作用提供了针对某些通路发生改变的癌症的潜在治疗策略，而这些通路在其他情况下可能被认为是难以成药的。基于现代CRISPR-Cas9技术的高通量筛选方法已经出现，并对于识别具有转化为生物学合理的癌症治疗策略潜力的新型合成致死相互作用以及能够指导患者选择的相关反应预测生物标志物至关重要。受PARP抑制剂在携带BRCA突变癌症患者中的临床成功的推动，靶向DNA损伤反应通路内多种合成致死相互作用的新型药物正在临床开发中，并且针对跨越表观遗传、代谢和增殖通路改变的合成致死相互作用的合理策略也已出现，正处于临床前后期和/或早期临床试验阶段。在本综述中，我们全面概述了用于合成致死药物发现和开发的既定技术和新兴技术，并讨论了针对此类相互作用的有前景的治疗策略。
