Drug-mediated inhibition of CDK4/CDK6 activity

Drug-mediated inhibition of CDK4/CDK6 activity Cyclin dependent kinases CDK4 and CDK6 regulate crucial steps in the G1 phase of the cell cycle that commit cells to transition to the S phase and ultimately divide. Many growth signaling pathways, frequently perturbed in cancer, converge on CDK4/CDK6 activation, thus driving cellular proliferation. This makes CDK4 and CDK6 promising targets for anti-cancer therapy. So far, three CDK4/6 inhibitors, palbociclib, ribociclib and abemaciclib, have been approved for clinical use and many others are at different stages of clinical testing. CDK4/6 inhibitors mainly have a cytostatic effect on tumor cells, but can also influence immune response to tumor by targeting immune system cells in the tumor microenvironment. While intact RB1, the main target of CDK4/6 during cell cycle progression, is in general considered to be a prerequisite for the success of CDK4/6-targeted anti-cancer therapy, the status of other, less explored CDK4/6 targets can also affect the treatment outcome. For review, please refer to Asghar et al. 2015, Klein et al. 2018, Álvarez-Fernández and Malumbres 2020, Petroni et al. 2020).