The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).
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Arora, M., Moser, J., Hoffman, T. E., Watts L. P. et al. Cell 186(12), pages 2628-2643.E21 (2023).
doi: doi.org/10.1016/j.cell.2023.05.013.
Summary of the findings
Summary of the findingsCDK2 is a core cell-cycle kinase that phosphorylates many substrates to drive progression through the cell cycle. CDK2 is hyperactivated in multiple cancers and is therefore an attractive therapeutic target. Here, we use several CDK2 inhibitors in clinical development to interrogate CDK2 substrate phosphorylation, cell-cycle progression, and drug adaptation in preclinical models. Whereas CDK1 is known to compensate for loss of CDK2 in Cdk2-/- mice, this is not true for acute inhibition of CDK2. Upon CDK2 inhibition, cells exhibit a rapid loss of substrate phosphorylation that rebounds within several hours. CDK4/6 activity backstops inhibition of CDK2 and sustains the proliferative program by maintaining Rb1 hyper-phosphorylation, active E2F transcription, and Cyclin A2 expression, enabling re-activation of CDK2 in the presence of drug. Our results augment our understanding of CDK plasticity and indicate that co-inhibition of CDK2 and CDK4/6 may be required to suppress adaptation to CDK2 inhibitors currently under clinical assessment.
**This abstract and figure were published in Cell, Volume 186, Issue 12, Arora, M. et al., Rapid adaptation to CDK2 inhibition exposes intrinsic cell-cycle plasticity, 2628 – 2643.e21, Copyright Elsevier (2023).
