Abstract 6950: VRK1 as a novel therapeutic target in small cell neuroendocrine carcinoma of the uterine cervix via mitochondrial dysfunction
Authors: Mariya Kobayashi, Satoshi Nakagawa, Yusuke Ishii, Yuji Kamei, Mizuki Kanda, Tatsuo Masuda, Mamoru Kakuda, Kosuke Hiramatsu, Tadashi Iwamiya, Shinya Matsuzaki, Masahiro Inoue, Yutaka Ueda
Journal: Cancer Research (2025)

Abstract [Objective] Small cell neuroendocrine carcinoma of the uterine cervix (SCNEC) is a rare cancer with a poor prognosis, highlighting the pressing need for effective pharmacotherapies. Our previous proteomic analysis identified vaccinia-related kinase 1 (VRK1) as one of the proteins highly expressed in SCNEC compared to squamous cell carcinoma (SCC) and adenocarcinoma (AC). VRK1 is a member of the VRK family of Ser-Thr kinases, and its overexpression is associated with poor prognosis in various cancers. It is also expected to be a potential synthetic-lethal drug target in VRK2-low/null cancers. This study aims to investigate the potential of VRK1 as a therapeutic target for SCNEC. [Methods] To examine VRK1 and VRK2 expression levels across different histological types of cervical cancer, immunohistochemistry was performed on clinical samples, including five SCNEC cases, 34 SCC cases, and seven AC cases. The effect of VRK1 on tumor growth was assessed in vitro (2D and 3D cultures) and in vivo (xenograft model) by shRNA-mediated knockdown of VRK1 (shVRK1) and its control (shCont). Gene Set Enrichment Analysis (GSEA) was conducted on RNA-seq data extracted from mouse xenograft tumors to compare shCont and shVRK1. Conditions with exposure to reactive oxygen species (ROS) were generated using hydrogen peroxide (H2O2). Mitochondrial function was evaluated through changes in mitochondrial membrane potential and mitochondrial protein expression. [Results] VRK1 expression exhibited variability in SCC and AC but was consistently high across all SCNEC samples. In 2D cultures, VRK1 knockdown demonstrated limited effects on cell proliferation; however, it significantly inhibited tumor growth in 3D cultures and in vivo xenograft models. GSEA revealed that mitochondrial translation and gene expression pathways were the most suppressed in shVRK1 tumors compared to shCont. Subsequent in vitro and in vivo experiments revealed that VRK1 knockdown had a stronger tumor growth inhibitory effect under conditions with exposure to ROS, driven by the combined influence of the tumor microenvironment and the tumor's high energy metabolism, and this was accompanied by mitochondrial dysfunction. Furthermore, VRK2 expression, a potential biomarker of VRK1's effects, was confirmed to be characteristically low in SCNEC. [Conclusion] SCNEC is characterized by high VRK1 expression and low VRK2 expression. VRK1 knockdown suppresses tumor growth via mitochondrial dysfunction, particularly in vivo. These findings suggest that VRK1 is a promising therapeutic target for the treatment of SCNEC. Citation Format: Mariya Kobayashi, Satoshi Nakagawa, Yusuke Ishii, Yuji Kamei, Mizuki Kanda, Tatsuo Masuda, Mamoru Kakuda, Kosuke Hiramatsu, Tadashi Iwamiya, Shinya Matsuzaki, Masahiro Inoue, Yutaka Ueda. VRK1 as a novel therapeutic target in small cell neuroendocrine carcinoma of the uterine cervix via mitochondrial dysfunction [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 6950.