Targeted drugs and precision medicine have transformed the landscape of cancer therapy and significantly improved patient outcomes in many cases. However, as therapies are becoming more and more tailored to smaller patient populations and acquired resistance is limiting the duration of clinical responses, there is an ever increasing demand for new drugs, which is not easily met considering steadily rising drug attrition rates and development costs. Considering these challenges drug repurposing is an attractive complementary approach to traditional drug discovery that can satisfy some of these needs. This is facilitated by the fact that most targeted drugs, despite their implicit connotation, are not singularly specific, but rather display a wide spectrum of target selectivity. Importantly, some of the unintended drug “off-targets” are known anticancer targets in their own right. Others are becoming recognized as such in the process of elucidating off-target mechanisms that in fact are responsible for a drug’s anticancer activity, thereby revealing potentially new cancer vulnerabilities. Harnessing such beneficial off-target effects can therefore lead to novel and promising precision medicine approaches. Here, we will discuss experimental and computational methods that are employed to specifically develop single target and network-based off-target repurposing strategies, for instance with drug combinations or polypharmacology drugs. By illustrating concrete examples that have led to clinical translation we will furthermore examine the various scientific and non-scientific factors that cumulatively determine the success of these efforts and thus can inform the future development of new and potentially lifesaving off-target based drug repurposing strategies for cancers that constitute important unmet medical needs.

靶向药物和精准医疗改变了癌症治疗的格局，并在许多情况下显着改善了患者的治疗效果。然而，随着治疗越来越适合较小的患者群体，并且获得性耐药限制了临床反应的持续时间，对新药的需求不断增加，考虑到药物损耗率和开发成本的稳步上升，这种需求并不容易满足。考虑到这些挑战，药物再利用是对传统药物发现的一种有吸引力的补充方法，可以满足其中一些需求。大多数靶向药物尽管具有隐含的含义，但并不是特别具体，而是显示出广泛的靶向选择性，这一事实促进了这一点。重要的，一些非预期的药物“脱靶”本身就是已知的抗癌靶点。在阐明实际上负责药物抗癌活性的脱靶机制的过程中，其他人正在被认可，从而揭示潜在的新癌症脆弱性。因此，利用这种有益的脱靶效应可以带来新颖且有前途的精准医学方法。在这里，我们将讨论用于专门开发单靶点和基于网络的脱靶再利用策略的实验和计算方法，例如药物组合或多药理学药物。