Abstract 4437: Pimitespib (TAS-116), an HSP90 inhibitor, overcomes resistance to androgen receptor pathway inhibitors in prostate cancer by simultaneously targeting several key resistance mechanisms

Abstract Background: Resistance to androgen receptor pathway inhibitors (ARPIs) poses a significant challenge in the treatment of metastatic castration-resistant prostate cancer (mCRPC). Key mechanisms driving ARPI resistance include androgen receptor (AR) overexpression, AR mutations, AR splice variants such as AR-V7, alternative glucocorticoid receptor (GR) signaling, and activation of the AKT pathway. Heat shock protein 90 (HSP90), a molecular chaperone essential for stabilizing several of the key proteins involved in these resistance-related mechanisms, has emerged as a compelling therapeutic target. Pimitespib (TAS-116), an HSP90 inhibitor approved in Japan for the treatment of gastrointestinal stromal tumors, holds potential for addressing ARPI resistance by disrupting these mechanisms through the inhibition of nuclear translocation and protein destabilization of AR and related factors. Materials and Methods: The effects of pimitespib were assessed in four human prostate cancer cell lines (LNCaP, VCaP, 22Rv1, and SAS MDV No.3). Cell proliferation was assessed using intracellular ATP measurements. Western blotting and quantitative reverse transcription polymerase chain reaction were used to analyze protein and gene expression levels of resistance markers, including AR, AR-V7, GR, AKT, as well as their downstream transcriptional targets. Subcellular localization of AR and GR was examined using Western blotting. Antitumor efficacy was evaluated in two castration-resistant prostate cancer (CRPC) xenograft models (LNCaP-Xeno-IL-6 and VCaP). Results: Pimitespib enhanced the efficacy of three ARPIs (enzalutamide, darolutamide, and abiraterone) in the four prostate cancer cell lines. Mechanistic analysis revealed that pimitespib rapidly inhibited nuclear translocation of AR and GR within 1 h of treatment. Additionally, pimitespib reduced the protein levels of AR, GR, AR-V7, and AKT, effectively reversing ARPI resistance. Gene expression analysis showed that pimitespib downregulated AR, AR-V7, and GR target genes. In the CRPC xenograft models, pimitespib potentiated the antitumor effects of the ARPIs, resulting in enhanced inhibition of tumor growth. Combination therapy using pimitespib with enzalutamide was well-tolerated, with no significant increase in toxicity. Conclusion: Pimitespib effectively addresses ARPI resistance in mCRPC by rapidly inhibiting AR and GR nuclear translocation and reducing the protein levels of AR, GR, AR-V7, and AKT. In addition, our findings highlight the potential of combining pimitespib with ARPIs for the treatment of mCRPC patients who have progressed on ARPI therapy. Citation Format: Hiromi Muraoka, Kazuhisa Minamiguchi, Akihiro Hashimoto, Hiroshi Sootome, Shuichi Ohkubo. Pimitespib (TAS-116), an HSP90 inhibitor, overcomes resistance to androgen receptor pathway inhibitors in prostate cancer by simultaneously targeting several key resistance mechanisms [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 4437.