Abstract 562: Role of kinesin and Bcl-2 protein association in prostate cancer therapeutic resistance to taxane chemotherapy

Abstract Introduction: Therapeutic resistance to taxane chemotherapy remains a key contributor to lethality in patients with metastatic castration resistant prostate cancer (mCRPC). Understanding the mechanisms that drive therapeutic resistance is critical to reduce prostate cancer mortality. Our previous studies demonstrated overexpression of the mitotic spindle protein kinesin (HSET) and the anti-apoptotic Bcl-2 in taxane resistant human prostate cancer cells, C4-2BDR. This study aims to understand the contribution of Bcl-2 and kinesin protein interactions and their co-targeting by cabazitaxel (2nd line taxane chemotherapy) and kinesin inhibitor ispinesib, to overcome therapeutic resistance in prostate cancer. Methods: Two prostate cancer cell lines were used, the LNCaP-Bcl-2 and the C4-2BDR. To investigate the role of Bcl-2 in resistance, LNCaP cells overexpressing Bcl-2 were treated with cabazitaxel and ispinesib as monotherapies and in combination. Treatment response was analyzed based on cell viability studies, and expression of HSET and Bcl-2 was assessed via Western blot. Immunoprecipitation of Bcl-2 was performed for proteomic analysis in C4-2BDR cells following cabazitaxel treatment. We subsequently evaluated the in vivo effect cabazitaxel in combination with ispinesib, on C4-2B xenograft growth and tumor evaluation by immunohistochemistry. Results: Time course and dose response studies revealed that overexpression of Bcl-2 in LNCaP cells in vitro conferred resistance to both cabazitaxel and ispinesib as monotherapies. Transient increase in expression of HSET was observed, while Bcl-2 expression was unchanged by treatment. However, the association between HSET and Bcl-2 was targeted by cabazitaxel after 24 hours in both parental and LNCaP-Bcl-2 cells. Proteomic analysis of Bcl-2 binding partners in C4-2BDR cells, revealed upregulation of pathways involved in cytoskeleton remodeling, ribosomal and translation pathways, and cell adhesions in response to treatment. In C4-2B xenograft models, combination therapy of cabazitaxel and ispinesib reduced tumor growth, compared to each drug alone. Tumors treated with combination therapy exhibited higher E-cadherin, and reduced vimentin and HSET immunoreactivity compared to other treatments, suggesting EMT reversion towards an epithelial phenotype that correlated with response. Conclusions: These studies suggest a functional Bcl-2 association with mitotic spindle protein, kinesin and proteins involved in cytoskeleton organization and remodeling, that might result in resistance to taxane chemotherapy. These findings are of therapeutic significance in identifying a potential targeting value of Bcl-2 association with HSET to increase the therapeutic vulnerability in advanced prostate tumors. Citation Format: Maddison Archer, Hamam Said, Sudeh Izadmehr, Nabila Zaman, Prerna R. Nepali, Goutam Chakraborty, Matthew D. Galsky, Wei Yang, Natasha Kyprianou. Role of kinesin and Bcl-2 protein association in prostate cancer therapeutic resistance to taxane chemotherapy [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 562.