CDK8/19 Enhances the Anti-tumor Efficacy of Gastric Cancer by Regulating PARP Inhibitor Sensitivity
10.13865/j.cnki.cjbmb.2025.07.1223
- VernacularTitle:CDK8/19通过调节PARP抑制剂敏感性改善胃癌抗肿瘤疗效
- Author:
Jun-Di WANG
1
;
Wan-Chang LIU
;
Jian-Song LIU
;
Tian-Run LI
;
Yan TIAN
;
Dan-Tong SUN
;
Ze-Nan FAN
;
Xiao-Man LI
;
Jia-Dong WANG
Author Information
1. 北京大学基础医学院放射医学系,北京大学国际癌症研究院,北京大学临床医学高等研究院,分子肿瘤学全国重点实验室,北京大学医学部,北京 100191;北京大学第一医院,肿瘤内科,北京 100034
- Publication Type:Journal Article
- Keywords:
CDK8/19;
poly(ADP-ribose)polymerase inhibitor(PARPi);
gastric cancer(GC);
syn-thetic lethal;
homologous recombination repair
- From:
Chinese Journal of Biochemistry and Molecular Biology
2025;41(9):1280-1297
- CountryChina
- Language:Chinese
-
Abstract:
Gastric cancer remains one of the most prevalent and lethal malignancies of the digestive tract worldwide,underscoring the urgent need for more effective targeted therapeutic strategies.Poly(ADP-ri-bose)polymerase(PARP)inhibitors have demonstrated remarkable efficacy in tumors with homologous recombination repair(HRR)deficiency;however,their clinical application in gastric cancer remains limited.Clinical evidence suggests that patients harboring Helicobacter pylori infection in combination with HRR gene mutations exhibit a significantly elevated risk of developing gastric cancer,thereby supporting the potential benefit of PARP inhibition in this setting.In this study,a kinase inhibitor library was screened in combination with the PARP inhibitor olaparib in gastric cancer cells.And we identify the cy-clin-dependent kinase 8/19(CDK8/19)inhibitor Senexin A as a compound that synergistically enhances the cytotoxic effect of PARP inhibition(P<0.05).Phenotypic validation using CCK-8 and colony for-mation assays demonstrated that the combination treatment significantly suppressed cellular proliferation and clonogenic potential compared to either monotherapy(P<0.0001).Mechanistically,alkaline comet assays revealed a significant increase in DNA damage in the combination treatment group relative to either single-agent group(P<0.0001),suggesting that the synergistic effect results from the exacerbation of DNA damage via impaired DNA repair mechanisms.In addition,treatment with CDK8/19 inhibitors a-lone markedly increased the formation of γH2AX and 53BP1 foci in irradiated gastric cancer cells(P<0.0001),indicating inhibition of DNA damage repair pathways.Transcriptome sequencing further re-vealed that CDK8/19 inhibition impacts critical cellular pathways,including DNA repair,cell cycle reg-ulation,and RNA splicing.Co-immunoprecipitation assays confirmed that inhibition of CDK8/19 kinase activity significantly reduces the phosphorylation level of PARP1,suggesting a potential regulatory inter-action.Immunohistochemical analysis of tumor and adjacent non-tumor tissues from gastric cancer pa-tients demonstrated that CDK8 is significantly overexpressed in tumor tissues,supporting its potential as both a prognostic biomarker and a therapeutic target.Collectively,this study elucidates a mechanistic ba-sis by which CDK8/19 inhibition enhances the sensitivity of gastric cancer cells to PARP inhibitors.These findings provide a strong rationale for the combined use of CDK8/19 and PARP inhibitors as a tar-geted therapeutic strategy and offer promising translational implications for advancing personalized medi-cine in gastric cancer treatment.
