Clinical significancy of WNT pathway inhibition in various cancers

Abstract

The tumor microenvironment (TME) plays an important role in the cell cycle. There is a correlation between the Wnt/B–catenin signaling pathway and TME. This article reviews methods of inhibiting Wnt Pathway, a useful process in the treatment of various cancers. Compounds of Wnt/β–Catenin Signaling Pathway, such as TCF–1, have an impact on the differentiation and migration of CD8⁺ T cells. CCL4 expression is regulated by the beta–catenin protein to recruit CD103+ dendritic cells, which enables CD8+ T cell activation. Inhibition of the Wnt/β–catenin pathway has an impact on ovarian cancer patients’ prognosis, reducing the development of ovarian cancer. Research shows that inhibition of the pathway with the use of the LGK974 inhibitor may boost immunity, especially when applied with a Paclitaxel mix. After treatment, expression of the inhibitory receptors CTLA–4, TIM3, PD–1 on CD8+ T cells decreased. The combination of LGK974 and Paclitaxel can cause the death of tumor cells and significantly inhibit their proliferation. The application of dose–dense Paclitaxel avoids toxicity related to the maximum dose needed to protect the patient's immune system by increasing CD8+ TILs.  There are concerns regarding toxicity of the LGK 974, especially for cells dependent on the Wnt/β–catenin pathway to maintain homeostasis. Many Wnt/β–catenin pathway inhibitors are tested against colorectal cancer (CRC) with successful results. These include NSAIDs, porcupine inhibitors, tankyrase inhibitors, Wnt5A inhibitors, and disheveled protein inhibitors.The Wnt/β–catenin pathway, when expressed in Triple Negative Breast Cancer (TNBC), leads to the transition of epithelial to mesenchymal cells. In early clinical development, there are multiple inhibitors (ex. KYA1797K) targeting the Wnt/β–catenin pathway in TNBC cells, which could become a viable anticancer strategy.