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Abstract Renal cell carcinoma (RCC) is a common type of kidney cancer. The overall 5-year survival rate is 74%, but it drops to only 8% for Stage 4 cancers. Several treatments are available for metastatic RCC, including tyrosine kinase inhibitors, mTOR inhibitors, and immune checkpoint inhibitors. However, these treatments have limited success. VLX1570 is an inhibitor of deubiquitylating enzymes UCHL5/USP14 that is currently in Phase I clinical trials. It has shown promise in various cancer models, but its effects on RCC have not been reported. This study investigated the impact of UCHL5/USP14 expression on tumor progression and patient survival in a clinical cohort. The results showed that VLX1570 induced apoptosis and cell cycle arrest in RCC cells, leading to reduced cell viability. Additionally, VLX1570 synergized with temsirolimus in vitro, likely by inhibiting PCNA. Moreover, the combination treatment suppressed tumor growth in vivo more effectively than either VLX1570 or temsirolimus alone. These findings suggest that UCHL5/USP14 plays a role in RCC progression and prognosis, making it a promising therapeutic target for overcoming drug resistance in this cancer. Citation Format: Kuan-Lin Kuo, Po-Ming Chow, Chen-Hsun Hsu, Shih-Ming Liao, Yen-Ling Chiu, Jun-Ren Dong, Tzu-Yao Ke, Kuo-How Huang. An inhibitor of deubiquitinating enzyme UCHL5/USP14, VLX1570, enhances the cytotoxic effects of temsirolimus by suppressing PCNA in uuman renal cell carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 6066.
Kuo et al. (Fri,) studied this question.