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Targeting FZD6 creates therapeutically actionable vulnerabilities for advanced prostate cancer
Yongtao Li1, Zhicheng Zhou1, Yiqun Zhang2
1Department of Urology, University of Washington, Seattle, WA, USA.
Oncogene
|November 25, 2025
Summary
Targeting Frizzled 6 (FZD6) receptor, highly expressed in advanced prostate cancers, suppresses tumor growth and enhances DNA damage repair. This discovery offers a promising therapeutic strategy for prostate cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Signaling
Background:
- Wnt signaling pathway components, including ligands and frizzled (FZD) receptors, are implicated in prostate cancer progression.
- Upregulation or mutation of Wnt signaling is common in advanced prostate cancers, promoting proliferation, metastasis, and therapy resistance.
- Targeting the entire Wnt pathway is challenging due to potential tissue toxicity.
Purpose of the Study:
- To investigate the role of specific Frizzled receptors in advanced prostate cancer.
- To evaluate Frizzled 6 (FZD6) as a potential therapeutic target in prostate cancer.
- To elucidate the mechanisms by which FZD6 influences prostate cancer growth and DNA repair.
Main Methods:
- Analysis of FZD receptor expression and amplification in advanced prostate cancer tissues.
- In vitro and in vivo studies involving FZD6 knockdown in prostate cancer cell lines and patient-derived xenograft models.
- Assessment of DNA double-strand break (DSB) repair, SRC kinase and STAT3 activity, and WEE1/PLK1 signaling following FZD6 knockdown.
- Kinome-wide CRISPR-Cas9 knockout screen to identify synergistic drug targets with FZD6 inhibition.
Main Results:
- FZD6 is the most highly expressed and frequently amplified Wnt receptor in advanced human prostate cancers.
- FZD6 knockdown significantly suppresses prostate cancer cell growth in vitro and in vivo.
- FZD6 knockdown impairs DNA double-strand break (DSB) repair by downregulating WEE1 via PLK1, linked to reduced SRC kinase and STAT3 activity.
- FZD6 inhibition enhances prostate cancer cell sensitivity to genotoxic agents and sensitizes cells to PKMYT1 inhibition.
Conclusions:
- Targeting FZD6, a specific Wnt receptor highly expressed in prostate cancer, offers significant therapeutic potential.
- FZD6 inhibition disrupts prostate cancer cell proliferation and DNA repair mechanisms.
- Combining FZD6 inhibition with genotoxic agents or PKMYT1 inhibitors represents a promising therapeutic strategy for advanced prostate cancer.
