Chen Chu, Shanshan Zheng, Ning Mitchell, Zheqi Li, Xixi Zhang, Xiaowei Wu, Tian Zhang, Fabin Dang, Wojciech Michowski, Aleksandra Kolodziejczyk, Miranda L Xu, Krzysztof W Kotowski, Zhe Yang, Diego Martinez-Alonso, Joao Paulo, Jindan Sheng, Jane A Kirby, Finn Groezinger, Yubin Zhou, Miao He, Yoshinaga Ito, Anushree C Gulvady, Michael I Cole, Pierre Foidart, Jun Nishida, Xiaohan Ning, Samanta Sharma, Jan M Suski, Anne Fassl, Yu Zhou, Yan Geng, Wenyi Wei, Steven P Gygi, Kornelia Polyak, Kai W Wucherpfennig, Piotr Sicinski
The cyclin E-cyclin-dependent kinase 2 (CDK2) complex is a component of mammalian cell-cycle machinery that drives cell division. Hyperactivation of cyclin E-CDK2 is frequent in human cancers. Small-molecule CDK2 inhibitors are tested in clinical trials for cancer patients. Here, we report that cyclin E-CDK2 has a cell-cycle-independent function in regulating the global transcriptional program of cancer cells. CDK2 phosphorylates bromodomain-containing protein-4 (BRD4) and regulates its chromatin association. Overexpression of cyclin E and the resulting activation of CDK2 in cancer cells alter the cancer cell transcriptome, repress the expression of interferon-stimulated genes, and confer resistance to immunotherapy. Conversely, CDK2 inhibition has the opposite effect and augments the efficacy of immune checkpoint blockade. CDK2 inhibition also increases tumor infiltration by dendritic cells (DCs) and enhances antigen cross-presentation to CD8 T cells. These studies reveal an additional function of cyclin E-CDK2 in tumorigenesis and identify inhibition of CDK2 with clinically available compounds as a strategy for enhancing immune checkpoint blockade.