Discrete vulnerability to pharmacological CDK2 inhibition is governed by heterogeneity of the cancer cell cycle

Nat Commun. 2025 Feb 9;16(1):1476. doi: 10.1038/s41467-025-56674-4.

Abstract

Cyclin dependent kinase 2 (CDK2) regulates cell cycle and is an emerging target for cancer therapy. There are relatively small numbers of tumor models that exhibit strong dependence on CDK2 and undergo G1 cell cycle arrest following CDK2 inhibition. The expression of P16INK4A and cyclin E1 determines this sensitivity to CDK2 inhibition. The co-expression of these genes occurs in breast cancer patients highlighting their clinical significance as predictive biomarkers for CDK2-targeted therapies. In cancer models that are genetically independent of CDK2, pharmacological inhibitors suppress cell proliferation by inducing 4N cell cycle arrest and increasing the expressions of phospho-CDK1 (Y15) and cyclin B1. CRISPR screens identify CDK2 loss as a mediator of resistance to a CDK2 inhibitor, INX-315. Furthermore, CDK2 deletion reverses the G2/M block induced by CDK2 inhibitors and restores cell proliferation. Complementary drug screens define multiple means to cooperate with CDK2 inhibition beyond G1/S. These include the depletion of mitotic regulators as well as CDK4/6 inhibitors cooperate with CDK2 inhibition in multiple phases of the cell cycle. Overall, this study underscores two fundamentally distinct features of response to CDK2 inhibitors that are conditioned by tumor context and could serve as the basis for differential therapeutic strategies in a wide range of cancers.

MeSH terms

  • Animals
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • CDC2 Protein Kinase / genetics
  • CDC2 Protein Kinase / metabolism
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation* / drug effects
  • Cyclin B1 / genetics
  • Cyclin B1 / metabolism
  • Cyclin E / genetics
  • Cyclin E / metabolism
  • Cyclin-Dependent Kinase 2* / antagonists & inhibitors
  • Cyclin-Dependent Kinase 2* / genetics
  • Cyclin-Dependent Kinase 2* / metabolism
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Mice
  • Neoplasms / drug therapy
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism
  • Protein Kinase Inhibitors / pharmacology

Substances

  • Cyclin-Dependent Kinase 2
  • CDK2 protein, human
  • Protein Kinase Inhibitors
  • Oncogene Proteins
  • Cyclin-Dependent Kinase Inhibitor p16
  • CCNE1 protein, human
  • Cyclin E
  • Cyclin B1
  • CDC2 Protein Kinase
  • CDKN2A protein, human
  • CDK1 protein, human
  • CCNB1 protein, human