The first wave of genetically targeted therapies for cancer focused on drugging gene products that are recurrently mutated in specific cancer types. However, mutational analysis of tumours has largely been exhausted as a strategy for the identification of new cancer targets that are druggable with conventional approaches. Furthermore, some known genetic drivers of cancer have not been directly targeted yet owing to their molecular structure (undruggable oncogenes) or because they result in functional loss (tumour suppressor genes). Functional genomic screening based on the genetic concept of synthetic lethality provides an avenue to discover drug targets in all these areas. Although synthetic lethality is not a new idea, recent advances, including CRISPR-based gene editing, have made possible systematic screens for synthetic lethal drug targets in human cancers. Such approaches have broad potential to drive the discovery of the next wave of genetic cancer targets and ultimately the introduction of effective medicines that are still needed for most cancers.

中文翻译：

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合成杀伤力可作为癌症药物靶标发现的引擎。

癌症的遗传靶向疗法的第一波重点是对在特定癌症类型中反复突变的基因产物进行药物治疗。然而，对肿瘤的突变分析已在很大程度上被耗尽，作为鉴定可以用常规方法治疗的新癌症靶标的策略。此外，由于其分子结构（不可治疗的癌基因）或由于它们导致功能丧失（肿瘤抑制基因），因此尚未将某些已知的癌症遗传驱动因素直接作为目标。基于合成致死性遗传概念的功能基因组筛选为在所有这些领域中发现药物靶标提供了途径。尽管合成杀伤力不是一个新主意，但最近的进展包括基于CRISPR的基因编辑，使得系统筛选人类癌症中的合成致死性药物成为可能。这些方法具有广泛的潜力，可以推动发现下一波遗传癌症靶标，并最终引入大多数癌症仍然需要的有效药物。