Cyclin-dependent kinase 2 (CDK2) inhibitors and others novel CDK inhibitors (CDKi) in breast cancer: clinical trials, current impact, and future directions

Crit Rev Oncol Hematol. 2024 Apr:196:104324. doi: 10.1016/j.critrevonc.2024.104324. Epub 2024 Mar 8.

Abstract

Aberrant cyclin-dependent kinase 2 (CDK2) activation has been identified as a main resistance mechanism to CDK4/6 inhibition in hormone-receptor positive (HR+) breast cancer. Additionally, consistent preclinical evidence states its crucial role in MYC and CCNE1 overexpressed cancer survival, such as triple-negative breast cancers (TNBC), thus representing an appealing and relatively unexplored target treatment opportunity. Despite emerging initial results of novel CDK2 inhibitors (CDK2i) activity, a comprehensive outcomes collection is currently absent from the scientific literature. We aim to provide an overview of ongoing clinical trials involving CDK2i in the context of metastatic breast cancer (mBC), either as monotherapy or in combination with other agents. The review extends beyond CDK2i to encompass novel emerging CDK4 inhibitors, combined CDK2/4/6 inhibitors, and the well-known pan-CDK inhibitors including those specifically directed at CDK2. Delving into the results, we critically appraise the observed clinical efficacy and offer valuable insights into their potential impact and future applications.

Keywords: Breast cancer (BC); Cyclin-dependent; Cyclin-dependent kinase 2 inhibitor (CDK2i); Cyclindependent; Kinase 2/4/6 inhibitor (CDK2/4/6i); Kinase 4 inhibitor (CDK4i); Metastatic breast cancer (mBC); Pan-Cyclin-dependent kinase inhibitor (Pan-CDKi).

Publication types

  • Review

MeSH terms

  • Breast Neoplasms* / pathology
  • Cell Cycle Checkpoints
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • Female
  • Humans
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Triple Negative Breast Neoplasms* / drug therapy

Substances

  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase 4
  • Protein Kinase Inhibitors
  • Cyclin-Dependent Kinase 6
  • CDK2 protein, human