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  • Title: Co-targeting p53-R249S and CDK4 synergistically suppresses survival of hepatocellular carcinoma cells.
    Author: Wang H, Liao P, Zeng SX, Lu H.
    Journal: Cancer Biol Ther; 2020; 21(3):269-277. PubMed ID: 31747859.
    Abstract:
    p53-R249S (p53-RS) is frequently detected in human hepatocellular carcinoma (HCC) that is highly associated with hepatitis B infection and aflatoxin B1 exposure. Our previous study showed that CDK4/Cyclin D1 phosphorylates p53-RS at the cancer-derived Ser249 and promotes its interaction with c-Myc in the nucleus, consequently enhancing c-Myc-dependent ribosomal biogenesis and HCC cell proliferation. Here we explored the possibility of co-targeting CDK4 and p53-RS with available small molecule inhibitors as a potential combined therapy for HCC that harbor p53-RS. Indeed, co-treatment of p53-RS-containing, but not wild-type p53 or p53-null, HCC cells with PD-0332991 (PD), a CDK4/6 inhibitor, and CP-31398 (CP), a compound that can restore the intrinsic conformation and transcriptional activity of mutant p53, drastically repressed the c-Myc activation function of p53-RS. This combination of PD with CP exhibited a synergistic effect on the inhibition of HCC cell growth in a p53-RS dependent manner, especially at a lower dose. These results suggest that co-targeting CDK4 and p53-RS can serve as a potential approach for the development of an effective therapy for HCC that harbor p53-RS.
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