Wnt/β-catenin signaling in cancers and targeted therapies

Abstract

Wnt/β-catenin signaling has been broadly implicated in human cancers and experimental cancer models of animals. Aberrant activation of Wnt/β-catenin signaling is tightly linked with the increment of prevalence, advancement of malignant progression, development of poor prognostics, and even ascendence of the cancer-associated mortality. Early experimental investigations have proposed the theoretical potential that efficient repression of this signaling might provide promising therapeutic choices in managing various types of cancers. Up to date, many therapies targeting Wnt/β-catenin signaling in cancers have been developed, which is assumed to endow clinicians with new opportunities of developing more satisfactory and precise remedies for cancer patients with aberrant Wnt/β-catenin signaling. However, current facts indicate that the clinical translations of Wnt/β-catenin signaling-dependent targeted therapies have faced un-neglectable crises and challenges. Therefore, in this study, we systematically reviewed the most updated knowledge of Wnt/β-catenin signaling in cancers and relatively targeted therapies to generate a clearer and more accurate awareness of both the developmental stage and underlying limitations of Wnt/β-catenin-targeted therapies in cancers. Insights of this study will help readers better understand the roles of Wnt/β-catenin signaling in cancers and provide insights to acknowledge the current opportunities and challenges of targeting this signaling in cancers.

Fig. 1

The extracellular components and signaling transduction of Wnt/β-catenin signaling. In this figure, we do not distinguish the autocrine or paracrine patterns of Wnt ligands

Fig. 2

The membrane-linked components and signaling transduction of Wnt/β-catenin signaling. Ub ubiquitin, ① the switch-on of Fzd/Lrp ubiquitination, ② the switch-ff of Fzd/Lrp ubiquitination via Rspo function

Fig. 3

The intracellular components and signaling transduction of Wnt/β-catenin signaling

Fig. 4

The structural illustration of human β-catenin protein. In this figure we mainly demonstrated the important PPI binding domains and phosphorylation sites of β-catenin. This image was modified from a published research.

Fig. 5

The statistical summary of up-to-date registered clinical trials of targeted therapies via targeting Wnt/β-catenin signaling in cancers. The left panel indicated the stages and the right one showed the phases of clinical trials. P1 phase I, P1b phase IB, P2 phase 2. All clinical trials included were updated until May 2021

Fig. 6

The overview of status quo registered clinical trials of Wnt/β-catenin signaling-dependent targeted therapies in cancers (updated in May 2021). Within the boxed diagram, the first lane provided the numbers of clinical trials for the specific type of cancers in all clinical trials. From the second to the fifth lane, we provided the types of drugs as SMIs, mAbs, Peptides, and others, and the parts that follow the colon indicted the names of drugs and the targeted components of Wnt/β-catenin signaling were shown in the brackets