Huang Dayin, Xiong Zhizhong, Zhong Bin, Li Xianwen, Mohamed Saddam Ahmed, Sun Jiachen, Xu Haoyang, Guo Jianping, Deng Zijian, Li Xianzhe, Almhanna Khaldoun, Chen Yonghe, Lian Lei
Department of General Surgery (Department of Gastrointestinal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
J Gastrointest Oncol. 2025 Jun 30;16(3):823-839. doi: 10.21037/jgo-2025-392. Epub 2025 Jun 23.
BACKGROUND: Gastric cancer (GC) is a leading cause of cancer-related mortality worldwide. Oxaliplatin (OXA) based therapy plus/minus targeted therapy and immune check point inhibitors is the standard first-line treatment for advanced GC; however, its clinical efficacy is often hindered by the development of drug resistance. Cyclin-dependent kinase 12 (CDK12), a transcriptional regulator linked to DNA repair, plays a crucial role in transcription, cancer progression as well as drug resistance, where its exact role is unclear. In this study, we will investigate the role of CDK12 in GC progression and its potential as a therapeutic target specifically to enhance the efficacy of OXA. METHODS: CDK12 expression in GC tissues was analyzed by quantitative polymerase chain reaction (qPCR) and tissue microarrays (TMAs). A Kaplan-Meier survival analysis was conducted to assess the relationship between CDK12 levels and clinical outcomes. The effect of the CDK12 inhibitor combined with OXA was evaluated through and models. RNA-sequencing and western blots were used to investigate the molecular mechanisms of CDK12 inhibitor sensitizing OXA. RESULTS: CDK12 exhibited significant amplification frequency in GC. The Mendelian-randomization analysis revealed a positive causal association between elevated CDK12 expression and an increased risk of GC. Additionally, CDK12 was significantly overexpressed in GC tissues compared with adjacent normal tissues, and its high expression was significantly associated with a worse prognosis. The functional assays revealed that combining the CDK12 inhibitor THZ531 with OXA synergistically suppressed GC cell proliferation, induced apoptosis, and reduced colony formation , while substantially inhibiting tumor growth in xenograft models. Mechanistically, CDK12 inhibition disrupted MAPK signaling, leading to enhanced OXA-induced DNA damage and potentiated anti-tumor effects. CONCLUSIONS: Our findings suggest that CDK12 inhibition may represent a promising strategy for overcoming OXA resistance and improving GC treatment outcomes.
背景：胃癌（GC）是全球癌症相关死亡的主要原因。基于奥沙利铂（OXA）的治疗加/减靶向治疗和免疫检查点抑制剂是晚期GC的标准一线治疗方法；然而，其临床疗效常常受到耐药性发展的阻碍。细胞周期蛋白依赖性激酶12（CDK12）是一种与DNA修复相关的转录调节因子，在转录、癌症进展以及耐药性中起关键作用，但其确切作用尚不清楚。在本研究中，我们将研究CDK12在GC进展中的作用及其作为治疗靶点的潜力，特别是增强OXA的疗效。 方法：通过定量聚合酶链反应（qPCR）和组织微阵列（TMA）分析GC组织中CDK12的表达。进行Kaplan-Meier生存分析以评估CDK12水平与临床结果之间的关系。通过 和 模型评估CDK12抑制剂与OXA联合使用的效果。使用RNA测序和蛋白质印迹法研究CDK12抑制剂使OXA致敏的分子机制。 结果：CDK12在GC中表现出显著的扩增频率。孟德尔随机化分析显示CDK12表达升高与GC风险增加之间存在正因果关联。此外，与相邻正常组织相比，CDK12在GC组织中显著过表达，其高表达与较差的预后显著相关。功能试验表明，将CDK12抑制剂THZ531与OXA联合使用可协同抑制GC细胞增殖、诱导凋亡并减少集落形成 ，同时在异种移植模型中显著抑制肿瘤生长。从机制上讲，CDK12抑制破坏了MAPK信号传导，导致OXA诱导的DNA损伤增强并增强了抗肿瘤作用。 结论：我们的研究结果表明，抑制CDK12可能是克服OXA耐药性和改善GC治疗结果有前景的策略。
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