Rapid adaptation to CDK2 inhibition exposes intrinsic cell-cycle plasticity

• Published in: Cell Vol. 186; no. 12; pp. 2628 - 2643.e21
• Main Authors: Arora, Mansi, Moser, Justin, Hoffman, Timothy E., Watts, Lotte P., Min, Mingwei, Musteanu, Monica, Rong, Yao, Ill, C. Ryland, Nangia, Varuna, Schneider, Jordan, Sanclemente, Manuel, Lapek, John, Nguyen, Lisa, Niessen, Sherry, Dann, Stephen, VanArsdale, Todd, Barbacid, Mariano, Miller, Nichol, Spencer, Sabrina L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.06.2023
• Subjects: Animals; CDK plasticity; CDK2; CDK4/6; Cell Cycle - physiology; Cell Cycle Proteins - metabolism; Cell Division; cyclin A; Cyclin-Dependent Kinase 2 - genetics; Cyclin-Dependent Kinase 2 - metabolism; Cyclin-Dependent Kinases - metabolism; drug adaptation; Mice; Palbociclib; PF-06873600; PF-07104091; Phosphorylation; restriction point; Rb; CDK4/6; PF-06873600; restriction point; drug adaptation; CDK plasticity; CDK2; Palbociclib; cyclin A; PF-07104091
• DOI: 10.1016/j.cell.2023.05.013
• ISSN: 0092-8674

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. [Display omitted] •CDK2 inhibition (CDK2i) causes rapid loss of kinase activity followed by a rebound•CDK2i unmasks CDK4/6 activity beyond G1, reinforcing Rb hyperphosphorylation•The Rb-E2F axis remains engaged under CDK2i, driving cyclin A and CDK2 activity•Co-inhibiting CDK2 and CDK4/6 presents a strategy to force durable cell-cycle exit Selective CDK2 inhibition initially blocks substrate phosphorylation. However, because of a potent positive feedback loop and reinforcement by CDK4/6 activity, cells can rapidly overcome CDK2 inhibition to complete the cell cycle.