A New Wave of Targeting 'Undruggable' Wnt Signaling for Cancer Therapy: Challenges and Opportunities

Abstract

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.

Keywords: PROTAC; Wnt signaling; anti-sense oligonucleotide (ASO); antibody–drug conjugate (ADC); targeted cancer therapy; β-catenin.

Figure 1

Wnt signaling and its alteration in various cancers. Signal transduction of β-catenin-dependent and independent Wnt signaling. The frequencies of genetic alteration of individual Wnt signaling modules in indicated cancers were summarized.

Figure 2

Wnt signaling modulating agents in clinical trials for cancer treatment. Promising clinical agents targeting the Wnt signaling module were displayed along with their targets.

Figure 3

Targeting Wnt signaling pathway by the latest technologies. β-catenin targeted PROTACs (xStAx-VHL) recruits E3 ligase to β-catenin, inducing the degradation of β-catenin using the ubiquitin–proteasome system. Additionally, the molecular glue of β-catenin and its E3 ligase β-TrCP, NRX-252114, enhances the β-catenin degradation. ADCs (LGR5-mc-vc-PAB-MMAE, LRG5-NMs818, and PF-06647020) targeting LGR5- or PTK7-expressing Wnt responder cells bind to the target cells and release a cytotoxic drug to induce the cell death. ASO (LNA-modified ASO, β-catenin targeting ASO) binds to the target region of RNA and suppresses expression.