image: Targeting the WNT signaling pathway represents a promising strategy for cancer therapy. The field has evolved to include numerous inhibitors currently under preclinical and clinical investigation. These agents can be broadly classified based on their molecular targets, which include: (1) Porcupine inhibitors, (2) WNT/FZD antagonists, (3) LRP5/6 inhibitors, (4) DVL inhibitors, (5) TNKS inhibitors, (6) CK1 agonists, (7) β-catenin/TCF transcriptional complex inhibitors, and (8) CBP inhibitors.
Credit: Jing Li
The WNT signaling pathway, an evolutionarily conserved system crucial for tissue development and repair, is increasingly recognized as a double-edged sword in human health. While it governs essential processes like cell proliferation and differentiation, its dysregulation is a powerful driver of cancer, promoting tumor growth, metastasis, and resistance to therapy. A new comprehensive review in Molecular Biomedicine synthesizes the latest advances in understanding this pathway and the ongoing quest to harness it for cancer treatment. Despite the promise of WNT-targeted drugs, the review underscores the significant challenge of overcoming toxic side effects to unlock their full clinical potential.
The review systematically delineates the complex roles of WNT signaling, from its fundamental mechanisms to its involvement in various cancer types. It details the array of therapeutic strategies being developed, from inhibitors targeting key pathway components like PORCN and TNKS to novel antibodies and combination therapies. A central focus is the critical hurdle of "on-target" toxicity, where drugs intended to block WNT signaling in tumors also disrupt its vital functions in healthy tissues, leading to issues like bone fractures. The authors highlight innovative approaches to enhance safety, such as improving drug specificity, identifying predictive biomarkers, and combining WNT signaling inhibitors with other agents like immunotherapies. Ultimately, this work charts a course toward more precise and effective WNT-targeted cancer treatments.
Key highlights from the review include:
1. Systematic delineation of the complex Wnt signaling transduction: The article provides a detailed exposition of not only the canonical and non-canonical WNT signaling pathways and their dysregulation mechanisms but also maps the crosstalk network between WNT signaling and other pivotal pathways.
2. Exploration of WNT signaling roles across various cancers: With a focus on cancers including breast cancer, colorectal cancer, liver cancer, glioblastoma, and prostate cancer, this review delineates the specific contributions of both canonical and non-canonical WNT signaling to the pathogenesis of these malignancies.
3. WNT signaling targeting molecular agents from bench to bedside: The review offers a comprehensive discussion on molecular drugs targeting key components of the WNT pathway. It elaborates on their mechanisms of action, therapeutic efficacy, and adverse effects, while also investigating their status in clinical trials to evaluate the maturity of clinical WNT-targeting strategies.
4. Forward-looking perspective on the clinical application of WNT pathway targeting: The review proposes future directions for clinical translation, which include utilizing WNT pathway components as biomarkers for diagnosis and treatment monitoring, and exploring combination therapies with other modalities. These insights aim to inform and guide future clinical endeavors.
Prof. Li and her team hope their work will catalyze the development of novel therapeutic approaches that will ultimately benefit cancer patients.
Journal
Molecular Biomedicine
Article Title
WNT signaling in cancer: molecular mechanisms and potential therapies.
Article Publication Date
22-Oct-2025