2. Academic Validation
  3. Rapid adaptation to CDK2 inhibition exposes intrinsic cell-cycle plasticity

Rapid adaptation to CDK2 inhibition exposes intrinsic cell-cycle plasticity

  • Cell. 2023 May 29;S0092-8674(23)00532-9. doi: 10.1016/j.cell.2023.05.013.
Mansi Arora 1,  Justin Moser 1,  Timothy E Hoffman 1,  Lotte P Watts 1,  Mingwei Min 2,  Monica Musteanu 3,  Yao Rong 4,  C Ryland Ill 1,  Varuna Nangia 1,  Jordan Schneider 1,  Manuel Sanclemente 5,  John Lapek 6,  Lisa Nguyen 6,  Sherry Niessen 6,  Stephen Dann 6,  Todd VanArsdale 6,  Mariano Barbacid 3,  Nichol Miller 6,  Sabrina L Spencer 7
Affiliations

Affiliations

  • 1 Department of Biochemistry and BioFrontiers Institute, University of Colorado-Boulder, Boulder, CO 80303, USA.
  • 2 Department of Biochemistry and BioFrontiers Institute, University of Colorado-Boulder, Boulder, CO 80303, USA; Guangzhou Laboratory, Guangzhou, Guangdong, China.
  • 3 Experimental Oncology Group, Molecular Oncology Programme, Spanish National Cancer Research Centre, Madrid, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, 28029 Madrid, Spain.
  • 4 Department of Biochemistry and BioFrontiers Institute, University of Colorado-Boulder, Boulder, CO 80303, USA; Department of Molecular, Cellular, and Developmental Biology and BioFrontiers Institute, University of Colorado-Boulder, Boulder, CO 80303, USA.
  • 5 Experimental Oncology Group, Molecular Oncology Programme, Spanish National Cancer Research Centre, Madrid, Spain.
  • 6 Oncology Research & Development, Pfizer Worldwide Research & Development, San Diego, CA 92121, USA.
  • 7 Department of Biochemistry and BioFrontiers Institute, University of Colorado-Boulder, Boulder, CO 80303, USA. Electronic address: sabrina.spencer@colorado.edu.
PMID: 37267950 DOI: 10.1016/j.cell.2023.05.013
Abstract

CDK2 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 of 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 hyperphosphorylation, 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.

Keywords

CDK plasticity; CDK2; CDK4/6; PF-06873600; PF-07104091; Palbociclib; Rb; cyclin A; drug adaptation; restriction point.

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