Abstract 6811: Overcoming temsirolimus resistance in renal cell carcinoma: The potential of bAP15 inhibitor combination therapy

Abstract Renal cell carcinoma (RCC) is a prevalent form of kidney cancer with a high mortality rate, especially in advanced stages. While treatments like tyrosine kinase inhibitors, mTOR inhibitors, and immune checkpoint inhibitors exist, they often have limited efficacy. Temsirolimus, a clinically used mTOR inhibitor, provides a therapeutic option for advanced RCC by hindering cell growth and proliferation, but resistance to this drug can emerge. This study investigated the role of deubiquitylating enzymes UCHL5/USP14 in RCC progression and the potential of their inhibitor, bAP15, to overcome Temsirolimus resistance. bAP15 demonstrated potent anti-cancer activity in RCC cells by inducing apoptosis and cell cycle arrest. Importantly, bAP15 synergized with Temsirolimus in vitro, likely by inhibiting proliferating cell nuclear antigen (PCNA), and enhanced Temsirolimus efficacy in vivo. This combination therapy suppressed tumor growth more effectively than either agent alone. These preclinical findings highlight the potential of bAP15 to overcome Temsirolimus resistance in RCC by targeting UCHL5/USP14. Further research, including clinical trials, is necessary to evaluate the safety and efficacy of bAP15 in RCC patients. Citation Format: YI-JU Kao, Kuan-Lin Kuo, Shih-Ming Liao, Chen-Hsun Hsu, Yen-ling Chiu, Wei-Chou Lin, Kuo-How Huang, Po-Ming Chow. Overcoming temsirolimus resistance in renal cell carcinoma: The potential of bAP15 inhibitor combination therapy [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 6811.