Abstract B051: Targeting the IGF1–CYR61 Axis: A Novel Therapeutic Strategy for Aggressive Prostate Cancer

Abstract Prostate cancer (PCa) remains a leading cause of cancer-related mortality among men, with rising incidence and limited treatment options for metastatic disease. Cysteine-rich angiogenic inducer 61 (CYR61), a matricellular protein with an insulin-like growth factor-binding domain, has been implicated in tumorigenesis across multiple cancers, yet its role in PCa progression is not fully understood. Given the established involvement of insulin-like growth factor-1 (IGF1) in PCa and its association with therapy resistance and metastasis, this study investigated the molecular crosstalk between CYR61 and IGF1 in androgen-dependent and castration-resistant PCa cell lines (PC3, LNCaP, and 22Rv1). Silencing CYR61 via siRNA significantly impaired cell viability, proliferation, prostasphere formation, clonogenicity, and migration across all models. Mechanistically, CYR61 knockdown suppressed PI3K/AKT signaling without affecting MAPK activation and reduced AR-V7 expression in LNCaP cells, suggesting a role in splicing regulation. IGF1 treatment induced dynamic, cell line-specific changes in CYR61 expression, with early upregulation in PC3 and 22Rv1 cells and transient suppression in LNCaP cells, correlating with integrin α5/β1 modulation. Inhibition of PI3K/AKT signaling abrogated IGF1-induced CYR61 expression and proliferation, confirming pathway dependency. These findings reveal that IGF1 promotes PCa progression through CYR61 via PI3K/AKT signaling and integrin-mediated regulation, positioning CYR61 as a promising therapeutic target for limiting tumor growth and metastasis in aggressive PCa. Future directions include mapping CYR61 and IGF1 expression across epithelial, stromal, and immune compartments using single-nucleus RNA sequencing and exploring CYR61’s role in splicing regulation and therapeutic resistance. Additionally, integrating CYR61 inhibition with IGF1R or PI3K inhibitors may offer synergistic benefits, particularly in tumors with high CYR61 expression. These insights may inform biomarker development and targeted therapies for advanced PCa, especially in populations with elevated IGF1 signaling. Citation Format: Greisha L. Ortiz-Hernández, Carmina Patrick, Stefan Hinz, Mark A. LaBarge, Yun Rose Li, Susan L. Neuhausen. Targeting the IGF1–CYR61 Axis: A Novel Therapeutic Strategy for Aggressive Prostate Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr B051.