Abstract 1875: PBK expression promotes the aggressive phenotypes of mesothelioma

Abstract Mesothelioma is one of the most aggressive neoplasms worldwide that has a particularly poor prognosis. Novel therapeutic strategies to effectively treat patients with mesothelioma are urgently needed. We have previously discovered that oxytocin receptors (OXTR) are highly expressed in mesothelioma and that OXTR knockdown significantly decreases the proliferation of mesothelioma cells with high OXTR expression by disturbing the tumor cell cycle but targeted therapies utilizing the OXTR signaling system have not emerged. In this study, we performed quantitative proteomic profiling of two mesothelioma cell lines with high OXTR expression using mass spectrometry to investigate the downstream signals of OXTR in mesothelioma cells. We found that OXTR knockdown significantly downregulated PDZ-binding kinase (PBK)—a serine/threonine protein kinase belonging to the bispecific MAPKK family which is a crucial factor in cell mitosis, cell proliferation, migration, and anti-apoptosis and support of testicular functions. PBK knockdown significantly suppressed proliferation, migration, and colony formation in mesothelioma cells with high PBK expression, and decreased Akt and MAPK phosphorylation levels. We also found that a PBK inhibitor, OTS-514, suppressed the proliferation of these cell lines at low concentration. Furthermore, immunohistochemical analysis of PBK in surgical specimens obtained from patients with mesothelioma showed that high PBK expression was strongly associated with poor overall survival (log-rank test P=0.0031; hazard ratio 3.339 and 95% confidence interval 1.12-10.00) and recurrence-free survival (log-rank test P=0.0024; hazard ratio 3.355 and 95% confidence interval 1.25-9.04). In addition, the clinical significance of PBK expression was validated in mesotheliomausing datasets from TCGA. Multivariable Cox regression analysis, incorporating stage and OXTR mRNA expression, demonstrated that PBK mRNA expression was the strongest independent predictor of overall survival and the hazard ratio for PBK was higher than that for OXTR. Our findings indicate that PBK plays a crucial role in the aggressiveness of mesothelioma, making it a promising therapeutic target and potential prognostic biomarker for mesothelioma. Citation Format:Kazumi Hori, Ichidai Tanaka, Tatsuhiro Sato, Mika Sato, Yuta Kodama, Hideyuki Itoigawa, Yuichi Abe, Taketo Kato, Ayumu Taguchi, Mitsuo Sato, Yoshitaka Sekido, Toyofumi Fengshi Yoshikawa, Makoto Ishii. PBK expression promotes the aggressive phenotypes of mesothelioma [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 1875.