Abstract 233: Targeting Rho GTPases RAC1 and CDC42 in advanced prostate cancer cells

Abstract BACKGROUND: The androgen receptor (AR) plays a central role in the development and progression of prostate cancer. Standard treatment for advanced prostate cancer targets the AR using androgen deprivation therapy. Despite initial responses, patients eventually progress to androgen-independent disease with metastasis, raising the need for novel treatment options. GTPases regulate many metastasis-associated processes, including cell division, cell growth, cell migration, and cell adhesion. Novel inhibitors for GTPases are currently being evaluated for efficacy in metastatic breast cancer. However, little is known about their utility for other hormone-dependent cancers such as prostate cancer. We hypothesize that Rho GTPase inhibitor efficacy will vary between prostate cancer cell models based on AR expression status and metastatic potential. This study aims to determine the efficacy of nine compounds targeting the GTPase pathway in the setting of AR-positive compared to AR-negative prostate cancer cells. METHODS: AR-positive (LNCaP, 22rv1) and AR-negative (PC3, DU145) prostate cancer cell lines were used to evaluate the efficacy of nine novel Rho GTPase inhibitors. MTT viability assays were performed following exposure of cells to 0-100μM compound for 72 hours. Migration assays were performed using sublethal doses of select compounds for 3-5 days. Intracellular expression of Rho GTPase-associated proteins was evaluated using Western blot. RESULTS: Of the compounds analyzed, six had an IC50 in the nanomolar range. The most effective compound overall was CPV-337 (IC50: 6.5-108.6nM). AR-negative cell lines exhibited a higher sensitivity to EHOP-097 and MBQ-168 than AR-positive cell lines. Proteins associated with mechanotransduction were elevated in AR-negative compared to AR-positive cells. CONCLUSION: Our study demonstrates a central role for Rho GTPases in prostate cancer metastatic potential in the context of AR independence. ACKNOWLEDGEMENTS: These studies were supported by start-up funds provided to C.J.D.O. by the University of Puerto Rico Comprehensive Cancer Center in San Juan, Puerto Rico. Citation Format: Wilfred Fonseca Ferrer, Valeria Torres Matos, Carolina Restrepo Soto, Jessica Colon Gonzalez, Suranganie Dharmawardhane Flanagan, Cornelis P. Vlaar Stoop, Carlos Joel Diaz Osterman. Targeting Rho GTPases RAC1 and CDC42 in advanced prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 233.