An Integrated Mechanism of CDK2 and CDK4/6 Inhibition in Gastric Cancer Cells

Xu L, Wu S, Huang J, Guo R, Zheng M, Zhang Y and Wu X

Department of Physiology, Basic Medical College of Putian University, China
Department of Gastrointestinal Surgery, The First Hospital of Putian City, China
Department of Pathology, The First Hospital of Putian City, China
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Gastrointestinal Cancer Center, China
The School of Clinical Medicine, Fujian Medical University, China
These authors contributed equally to this work

^*Correspondance to: Xuelei Wu 

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Abstract:

Clinical studies demonstrate that cyclin-dependent kinase 4/6 inhibitors exhibit limited efficacy in gastric cancer. Cyclin E1, encoded by CCNE1 gene, contributes to intrinsic resistance to CDK4/6 inhibition in gastric cancer. In this study, we aimed to interrogate the potential application of CDK2/4/6i in gastric cancer. We found that CDK4/6 inhibition showed little to moderate potency in gastric tumor cell lines. In contrast, targeting CDK2/4/6 more potently inhibited cell proliferation and Rb-E2F signaling pathway. Mechanistically, a CDK2/4/6 inhibitor, PF-06873600, exert its effects on promoting cellular senescence via an integrated mechanism of cell cycle arrest and cellular senescence by upregulating nuclear factor kappa B (NF-κB) activity. Moreover, PF- 06873600 effectively inhibited Rb signaling and cell growth in GC cells over expressing CCNE1. Our preclinical data provide scientific rationale for co-targeting CDK2 and CDK4/6 in gastric cancer.

Keywords:

Cyclin-dependent kinase; Cell cycle arrest; NF-κB; Senescence

Cite the Article:

Xu L, Wu S, Huang J, Guo R, Zheng M, Zhang Y, et al. An Integrated Mechanism of CDK2 and CDK4/6 Inhibition in Gastric Cancer Cells. World J Surg Surgical Res. 2023; 6: 1483..