Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Jun 8;186(12):2628-2643.e21.
doi: 10.1016/j.cell.2023.05.013. Epub 2023 Jun 1.

Rapid adaptation to CDK2 inhibition exposes intrinsic cell-cycle plasticity

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
Free article

Rapid adaptation to CDK2 inhibition exposes intrinsic cell-cycle plasticity

Mansi Arora et al. Cell. .
Free article

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.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests The authors declare the following competing interests: S.L.S. received research funding from Pfizer Inc. for this collaboration. Pfizer authors were involved in the conceptualization and design of the study and performed their own data collection and analysis where indicated. Pfizer authors also provided input on the manuscript. M.B. received research funding from Pfizer Inc. S.D. and T.V. are stockholders of Pfizer Inc. A joint patent related to this work has been filed by the Regents of the University of Colorado and Pfizer Inc, with authors S.L.S., M.A., S.D., N.M., and T.V. Application number: PCT/IB2021/052894. Status of application: pending. Specific aspect of manuscript covered in the patent application involves co-treatment with CDK4/6 and CDK2 inhibitors to suppress adaptation to CDK2 inhibitors.

Publication types

Substances

LinkOut - more resources