Exploring the Wnt Pathway as a Therapeutic Target for Prostate Cancer

Abstract

Aberrant activation of the Wnt pathway is emerging as a frequent event during prostate cancer that can facilitate tumor formation, progression, and therapeutic resistance. Recent discoveries indicate that targeting the Wnt pathway to treat prostate cancer may be efficacious. However, the functional consequence of activating the Wnt pathway during the different stages of prostate cancer progression remains unclear. Preclinical work investigating the efficacy of targeting Wnt signaling for the treatment of prostate cancer, both in primary and metastatic lesions, and improving our molecular understanding of treatment responses is crucial to identifying effective treatment strategies and biomarkers that help guide treatment decisions and improve patient care. In this review, we outline the type of genetic alterations that lead to activated Wnt signaling in prostate cancer, highlight the range of laboratory models used to study the role of Wnt genetic drivers in prostate cancer, and discuss new mechanistic insights into how the Wnt cascade facilitates prostate cancer growth, metastasis, and drug resistance.

Advances in the Current Understanding of the Mechanisms Governing the Acquisition of Castration-Resistant Prostate Cancer

“…The altered Wnt pathway activity has been tied to malignant growth and progression in many tumor types [ 8 , 9 , 10 , 160 , 161 , 162 , 163 ]. Consistently, Wnt co-stimulation has been identified as a key driver of advanced PCA progression, with the Wnt pathway alterations being evident in 18% of the CRPC tumors [ 10 , 11 , 12 , 14 , 157 , 162 , 163 , 164 , 165 ]. Zi et al similarly detected the Wnt pathway activation in CRPC through RNA-seq and microarray analyses [ 165 ], and the KEGG pathway-enrichment analyses have highlighted the upregulation of key Wnt pathway components in PCA, following ADT exposure [ 166 ].…”

“…The Wnt pathway is separated into the classical Wnt/β-linked protein pathway, as well as the non-classical β-linked protein independent pathway [ 167 ]. In low-androgen settings, studies have found that AR interacts with the classical pathway, promoting the Wnt pathway activation [ 161 , 164 , 168 ]. On the one hand, a regulatory mechanism exists for Wnt and AR such that an increase or decrease in one can cause a reciprocal decrease or increase in the other.…”

“…On the other hand, the Wnt can interact with AR. For example, the downstream effector β-linked protein has also been identified as a coactivator of AR that is integral to the AR transcriptional complex formation, thereby promoting the acquisition of castration resistance [ 162 , 163 , 164 , 166 , 169 , 170 ].…”

Bridging the Gap in Understanding Bone Metastasis: A Multifaceted Perspective

“…The bone morphogenic protein (BMP) pathway, integral to mesenchymal stem cell differentiation, shows mixed roles in cancer, with pharmacological inhibition showing promise in certain bone metastasis models [ 187 , 188 ]. The Wnt signaling pathway, crucial in osteogenesis and cancer metastasis, offers potential therapeutic targets, including various inhibitors that are being investigated for their efficacy in prostate and breast cancers [ 189 ]. The CXCL12/CXCR4 axis, significant in bone metastasis regulation, has inhibitors in clinical trials showing potential to reduce cancer cell proliferation and migration [ 190 , 191 ].…”

Docetaxel Resistance in Castration-Resistant Prostate Cancer: Transcriptomic Determinants and the Effect of Inhibiting Wnt/β-Catenin Signaling by XAV939

“…In metastatic CRPC, increased expression of nuclear β-catenin and the target genes of the Wnt/β-catenin signaling pathway have been shown. It is thought that this signaling pathway underlies the acquisition of a selective advantage by cells under the influence of therapy [ 13 , 14 ]. One promising agent for study targeting Wnt/β-catenin signaling is the tankyrase inhibitor XAV939.…”