PD07-02 TARGETING WNT5A/FZD2 SIGNALING OVERCOMES RESISTANCE TO ENZALUTAMIDE IN ADVANCED PROSTATE CANCER

The Journal of Urology · 2022 · 1 citations

• Medicine
• Cancer research
• Internal medicine

You have accessJournal of UrologyCME1 May 2022PD07-02 TARGETING WNT5A/FZD2 SIGNALING OVERCOMES RESISTANCE TO ENZALUTAMIDE IN ADVANCED PROSTATE CANCER Shu Ning, Chengfei Liu, Wei Lou, Alan Lombard, Leandro D'Abronzo, Aiming Yu, Christopher Evans, and Allen Gao Shu NingShu Ning More articles by this author , Chengfei LiuChengfei Liu More articles by this author , Wei LouWei Lou More articles by this author , Alan LombardAlan Lombard More articles by this author , Leandro D'AbronzoLeandro D'Abronzo More articles by this author , Aiming YuAiming Yu More articles by this author , Christopher EvansChristopher Evans More articles by this author , and Allen GaoAllen Gao More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002526.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Androgen receptor (AR) blockade using antiandrogens is a mainstay for the treatment of castration resistant prostate cancer (CRPC). Unfortunately, drug resistance occurs frequently due to mechanisms that are not completely understood. Wnt5a, a representative ligand of non-canonical Wnt signaling, is expressed in circulating tumor cells from CRPC patients treated with enzalutamide. FZD2, the cognate frizzled receptor for Wnt5a, is the most commonly co-upregulated non-canonical Wnt receptor in prostate cancer. Here we determine the contribution of non-canonical Wnt5a/FZD2 to enzalutamide treatment resistance, and explore the potential of targeting Wnt5a/FZD2 to overcome antiandrogen resistance in castration resistant prostate cancer. METHODS: Wnt5a/FZD2 expression was examined in enzalutamide resistant C4-2B MDVR cells. Wnt5a and FZD2 expression were modulated using specific siRNAs. Cell growth, colony formation, migration and invasion were determined in vitro. RNA sequencing was analyzed on C4-2B MDVR cells with WNT5a/FZD2 knocked down; gene expression of non-canonical Wnt signaling, AR and AR-V7 signature genes were analyzed. A novel RNA bioengineered Wnt5a siRNA (tRNA-siWnt5A) was developed to target Wnt5a/FZD2 signaling. The effect of tRNA-siWnt5a on tumor growth and sensitivity to enzalutamide was evaluated in vitro and in vivo. RESULTS: Wnt5a and FZD2 are highly co-upregulated in CRPC patients and enzalutamide resistant C4-2B MDVR cells compared to parental C4-2B cells. Knocking down Wnt5a and FZD2 abrogates the increase of full-length AR and AR variant expression and diminishes the enrichment of genes involved in the non-canonical Wnt signaling pathway. Blocking Wnt5a and FZD2 using specific siRNAs suppresses prostate cancer cell growth, colony formation, migration and invasion. Wnt5a and FZD2 knockdown with siRNA resensitized C4-2B MDVR cells to enzalutamide treatment. Targeting Wnt5a using the bioengineered tRNA-siWnt5A inhibited the growth of enzalutamide resistant prostate cancer cells and resensitized cells to enzalutamide in vitro, and resistant CRPC LuCaP35CR PDX tumor growth in vivo. CONCLUSIONS: Our studies suggest that Wnt5a/FZD2 confers enzalutamide resistance and prostate cancer survival and proliferation. Targeting the non-canonical Wnt5a/FZD2 pathway suppresses tumors expressing high level of Wnt5a and FZD2, not only overcoming resistance but potentiating anti-tumor effects of enzalutamide in CRPC patients. Source of Funding: CA250082, CA 225836, DOD PC180180 © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e98 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Shu Ning More articles by this author Chengfei Liu More articles by this author Wei Lou More articles by this author Alan Lombard More articles by this author Leandro D'Abronzo More articles by this author Aiming Yu More articles by this author Christopher Evans More articles by this author Allen Gao More articles by this author Expand All Advertisement PDF DownloadLoading ...