Restoring order at the cell cycle border: Co-targeting CDK4/6 and CDK2

Overcoming resistance to CDK4/6 inhibitors is a major clinical challenge. In this issue of Cancer Cell, Freeman-Cook et al. study mechanisms of resistance to CDK4/6 inhibitors by employing a CRISPRa screen. They identify the cyclin E-CDK2 axis and Myc signaling as key pathways of resistance and develop PF-06873600, a selective CDK2/4/6 inhibitor. Overcoming resistance to CDK4/6 inhibitors is a major clinical challenge. In this issue of Cancer Cell, Freeman-Cook et al. study mechanisms of resistance to CDK4/6 inhibitors by employing a CRISPRa screen. They identify the cyclin E-CDK2 axis and Myc signaling as key pathways of resistance and develop PF-06873600, a selective CDK2/4/6 inhibitor. Expanding control of the tumor cell cycle with a CDK2/4/6 inhibitorFreeman-Cook et al.Cancer CellSeptember 13, 2021In BriefWhile CDK4/6 inhibitors are therapeutically beneficial in HR+ breast cancer, many patients experience therapy resistance. Freeman-Cook et al. find that in preclinical and clinical contexts, activation of the oncogene MYC can elicit CDK4/6 inhibitor resistance that converges on CDK2 activation. To mitigate these mechanisms CDK2/4/6 inhibitor PF-06873600 is developed, which has robust pharmacodynamic and tumor growth inhibitory activity in multiple models of cancer, preferentially those with elevated MYC activity. Full-Text PDF