Abstract 4286: CHK1 as a novel therapeutic target for pleural mesothelioma

Abstract Background: Pleural mesothelioma (PM) is a rare thoracic malignant tumor with poor prognosis. First line nivolumab plus ipilimumab prolonged overall survival compared to standard chemotherapy, however its clinical benefit is limited and development of therapeutic strategy with novel mechanisms is strongly desired. In this study, we focused on CHK1, one of the major molecules involved in the DNA damage repair, as a candidate for novel therapeutic target since one of the hallmarks of PM is DNA damage repair, such as BAP1 loss or TP53 mutation. Method: The prognostic impact of CHK1 mRNA expression on PM was analyzed using RNAseq data of The Cancer Genome Atlas (TCGA). The anti-tumor effect of CHK1 inhibitor using human PM cell lines were evaluated by MTT assay and annexin V assay. The protein expression was evaluated by Western blotting and the mRNA expression was evaluated by qRT-PCR. The anti-tumor effects of CHK1 inhibitor in vivo were evaluated with subcutaneous tumor model that was established by injecting mouse PM cells subcutaneously in immunodeficient Balb/c nu/nu mice, and the pleural carcinomatosis model that was also established with injecting the mouse PM cells into the intrapleural space of immunocompetent Balb/c mouse. Results: The low CHK1 expression group demonstrated significantly longer overall survival than the high CHK1 expression group in PM cases of TCGA. CHK1 inhibitor had anti-tumor effect and induced apoptosis in a dose-dependent manner. CHK1 inhibitor increased micronuclei formation, activated STING pathway, and induced mRNA expression of type I and II interferons, CCL5, and CXCL10, suggesting CHK1 inhibitor activated anti-tumor immune response. PD-L1 expression was also increased by CHK1 inhibitor. CHK1 inhibitor demonstrated significantly suppressed tumor growth combined with cisplatin compared to CHK1 inhibitor alone in the subcutaneous mouse model. Furthermore, CHK1 inhibitor combined with anti-PD-L1 antibody significantly prolonged overall survival in the pleural carcinomatosis model. Conclusion: The CHK1 inhibitor showed immunostimulatory effect on PM in addition to direct anti-tumor effect. Furthermore, the therapeutic benefit was enhanced when combined with cisplatin or anti-PD-L1 antibody. Citation Format: Kazumasa Akagi, Hirokazu Taniguchi, Hiromi Tomono, Midori Matsuo, Hiroshi Gyotoku, Shinnosuke Takemoto, Yasuhiko Nakao, Seiji Yano, Kazuto Ashizawa, Hiroshi Mukae. CHK1 as a novel therapeutic target for pleural 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 4286.