FZD6 Targeting Reveals Therapeutic Vulnerabilities in Prostate Cancer

Pan-Wnt inhibition causes dose-limiting toxicities in patients, prompting the search for more selective targets. The team analysed all 10 FZD receptors in prostate cancer and found FZD6 to be the most highly expressed and frequently amplified in castration-resistant, double-negative, and neuroendocrine disease, with expression correlating with adverse outcomes.

Using CRISPR-Cas9–mediated short hairpin RNA knockdown in multiple prostate cancer cell lines and patient-derived xenograft models, they demonstrated that FZD6 suppression reduced tumour growth by 18–56% whilst impairing both homologous recombination and non-homologous end-joining DNA repair pathways. Growth suppression occurred through reduced SRC kinase and STAT3 activities, whilst DNA repair deficiency resulted from WEE1 downregulation mediated by PLK1.

A pooled kinome-wide CRISPR-Cas9 knockout screen – systematically testing all ~763 human protein kinases – identified PKMYT1 as a synthetic lethal partner, with FZD6 knockdown cells showing 11-fold increased sensitivity to the PKMYT1 inhibitor lunresertib. Additionally, FZD6 knockdown enhanced cisplatin efficacy in castration-resistant xenografts, significantly improving survival.

The study was led by Yongtao Li and Li Xin from the University of Washington, Seattle. It was published in Oncogene today, 24 November 2025.