Department of Life Science, Gachon University, Seongnam 13120, Republic of Korea.
Department of Health Sciences and Technology, GAIHST, Lee Gil Ya Cancer and Diabetes Institute, Incheon 21999, Republic of Korea.
Cells. 2023 Apr 8;12(8):1110. doi: 10.3390/cells12081110.
Aberrant Wnt signaling activation is frequently observed in many cancers. The mutation acquisition of Wnt signaling leads to tumorigenesis, whereas the inhibition of Wnt signaling robustly suppresses tumor development in various in vivo models. Based on the excellent preclinical effect of targeting Wnt signaling, over the past 40 years, numerous Wnt-targeted therapies have been investigated for cancer treatment. However, Wnt signaling-targeting drugs are still not clinically available. A major obstacle to Wnt targeting is the concomitant side effects during treatment due to the pleiotropic role of Wnt signaling in development, tissue homeostasis, and stem cells. Additionally, the complexity of the Wnt signaling cascades across different cancer contexts hinders the development of optimized targeted therapies. Although the therapeutic targeting of Wnt signaling remains challenging, alternative strategies have been continuously developed alongside technological advances. In this review, we give an overview of current Wnt targeting strategies and discuss recent promising trials that have the potential to be clinically realized based on their mechanism of action. Furthermore, we highlight new waves of Wnt targeting that combine recently developed technologies such as PROTAC/molecular glue, antibody-drug conjugates (ADC), and anti-sense oligonucleotides (ASO), which may provide us with new opportunities to target 'undruggable' Wnt signaling.
异常的 Wnt 信号激活经常在许多癌症中观察到。Wnt 信号的突变获得导致肿瘤发生，而 Wnt 信号的抑制在各种体内模型中强烈抑制肿瘤的发展。基于靶向 Wnt 信号的出色临床前效果，在过去的 40 年中，已经研究了许多针对 Wnt 的治疗方法来治疗癌症。然而，Wnt 信号靶向药物在临床上仍不可用。靶向 Wnt 的一个主要障碍是由于 Wnt 信号在发育、组织稳态和干细胞中的多效性作用，在治疗过程中同时产生的副作用。此外，不同癌症环境中 Wnt 信号级联的复杂性阻碍了优化靶向治疗的发展。尽管 Wnt 信号的治疗靶向仍然具有挑战性，但随着技术的进步，已经不断开发替代策略。在这篇综述中，我们概述了当前的 Wnt 靶向策略，并讨论了根据其作用机制有潜力在临床上实现的最近有希望的试验。此外，我们强调了 Wnt 靶向的新浪潮，该浪潮结合了最近开发的技术，如 PROTAC/分子胶、抗体药物偶联物 (ADC) 和反义寡核苷酸 (ASO)，这可能为我们提供新的机会来靶向“不可成药”的 Wnt 信号。
