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Updated: May 23, 2025

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CDK2 inhibition produces a persistent population of polyploid cancer cells

Liliya Tyutyunyk-Massey1, Zibo Chen1, Xiuxia Liu1

  • 1Molecular Pharmacology Program and.

JCI Insight
|April 15, 2025
PubMed

Insights

Targeting cyclin-dependent kinase 2 (CDK2) causes cancer cell death, but some polyploid cells survive. Combined CDK2 and CDK1 or kinesin inhibition may eliminate resistant cancer cells.

Area of Science:

  • Oncology
  • Cell Biology
  • Genetics

Background:

  • Aneuploidy is a hallmark of cancer, contributing to chromosomal instability, drug resistance, and aggressive tumor progression.
  • Cyclin-dependent kinase 2 (CDK2) plays a critical role in cell cycle regulation and is implicated in cancer development.

Purpose of the Study:

  • To investigate the effects of CDK2 inhibition on aneuploid cancer cells and identify mechanisms of resistance.
  • To explore potential therapeutic strategies for overcoming resistance to CDK2 inhibition in lung cancer.

Main Methods:

  • Utilized time-lapse fluorescence microscopy with FUCCI probes to observe cell division dynamics in aneuploid lung cancer cells after CDK2 inhibition.
  • Performed RNA-Seq analysis to identify molecular pathways affected by CDK2 inhibition in different ploidy states.
  • Analyzed The Cancer Genome Atlas (TCGA) data to correlate CDK1 and KIF family member expression with patient survival.
  • Employed intravital microscopy to validate in vitro findings in a mouse model of lung cancer.

Main Results:

  • CDK2 inhibition induced anaphase catastrophe and apoptosis in aneuploid cells with supernumerary centrosomes.
  • A subset of polyploid cancer cells survived CDK2 inhibition, exhibiting resistance to apoptosis and continued proliferation.
  • RNA-Seq and TCGA analyses revealed enrichment of CDK1 and KIF pathways, with their overexpression linked to poor survival in lung cancer.
  • In vivo studies confirmed the emergence of apoptosis-resistant polyploid cancer cells following CDK2 inhibition in mice.

Conclusions:

  • CDK2 inhibition can trigger cell death in aneuploid cancer cells but leads to the selection of resistant polyploid populations.
  • Combined targeting of CDK2 with CDK1 or kinesin family members presents a promising therapeutic strategy to eliminate resistant polyploid cancer cells.
  • These findings have translational relevance for developing novel anti-cancer treatments for aggressive lung cancers.
Keywords:
Cell cycleOncologyPharmacologyTherapeutics

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