Inhibition of Wnt/β‐catenin pathway overcomes therapeutic resistance to abiraterone in castration‐resistant prostate cancer

This is the authors' abstract. We don't add key points for this paper.

Abiraterone acetate has been clinically approved for the treatment of patients with advanced-stage prostate cancer. It reduces testosterone production by blocking the enzyme cytochrome P450 17 alpha-hydroxylase. Despite improved survival outcomes with abiraterone, almost all patients develop therapeutic resistance and disease recurrence, progressing to a more aggressive and lethal phenotype. Bioinformatics analyses predicted activation of canonical Wnt/β-catenin and involvement of stem cell plasticity in abiraterone-resistant prostate cancer. Increased expression of androgen receptor (AR) and β-catenin and their crosstalk causes activation of AR target genes and regulatory networks for which overcoming acquired resistance remains a major challenge. Here we show that co-treatment with abiraterone and ICG001, a β-catenin inhibitor, overcomes therapeutic resistance and significantly inhibited markers of stem cell and cellular proliferation in abiraterone-resistant prostate cancer cells. Importantly, this combined treatment abrogated the association between AR and β-catenin; diminished SOX9 expression from the complex more prominently in abiraterone-resistant cells. In addition, combined treatment inhibited tumor growth in an in vivo abiraterone-resistant xenograft model, blocked stemness, migration, invasion, and colony formation ability of cancer cells. This study opens new therapeutic opportunity for advanced-stage castration-resistant prostate cancer patients.