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    Cancer Letters
    journal homepage:
    Original Articles
    Adefovir dipivoxil sensitizes colon cancer cells to vemurafenib by disrupting T the KCTD12-CDK1 interaction
    Jie Yanga, Wen Wen Xub, Pan Honga, Fei Yea, Xiao-Hui Huanga, Hui-Fang Hua, Qi-Hua Zhanga, Xin Yana, Bin Lia,∗∗, Qing-Yu Hea,∗
    a Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
    b Institute of Biomedicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, 510632, China
    Vemurafenib resistance
    Cell cycle
    Drug screening
    Protein-protein interaction
    Drug repurposing 
    Vemurafenib is a B-Raf V600E inhibitor that exerts significant inhibitory effects in melanoma but not in colon cancer, and the mechanism of vemurafenib resistance remains unclear. In this study, bioinformatics analysis of gene profiles in cancer cells treated with vemurafenib or its analog revealed that cell cycle progression is sig-nificantly affected by vemurafenib. We found that CDK1 is stably activated in the vemurafenib-resistant (VR) colon cancer sublines that we established, indicating that CDK1 activation is responsible for vemurafenib re-sistance. As the KCTD12-CDK1 interaction is necessary for CDK1 activation, we screened an FDA-approved drug library consisting of 616 compounds and identified that adefovir dipivoxil (AD), a nucleoside analog for treatment of HBV infections, disrupts the CDK1-KCTD12 interaction and induces G2 phase arrest in the cell cycle. Functional assays demonstrated that AD significantly inhibited colon cancer cell proliferation and tu-morigenesis both in vitro and in vivo with no observed side effects. Furthermore, AD sensitized vemurafenib-resistant colon cancer cells and tumor xenografts to vemurafenib. This study reveals that CDK1 activation in-duces vemurafenib resistance and that AD is a promising therapeutic strategy for colon cancer both as a single agent and in combination with vemurafenib.