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Updated: Aug 29, 2025

Live Cell Imaging to Assess the Dynamics of Metaphase Timing and Cell Fate Following Mitotic Spindle Perturbations
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Live Cell Imaging to Assess the Dynamics of Metaphase Timing and Cell Fate Following Mitotic Spindle Perturbations

Published on: September 20, 2019

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The spindle assembly checkpoint is a therapeutic vulnerability of CDK4/6 inhibitor-resistant ER+ breast cancer with

Isabel Soria-Bretones1,2,3, Kelsie L Thu1,4,5, Jennifer Silvester1

  • 1Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

Science Advances
|September 7, 2022
PubMed

Insights

A subset of estrogen receptor-positive (ER+) metastatic breast cancer resistant to CDK4/6 inhibitors develops defects in cell division. These defects make the cancer vulnerable to TTK inhibitors like CFI-402257.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) are a standard treatment for ER+ metastatic breast cancer.
  • Acquired resistance to CDK4/6i is a significant clinical challenge, necessitating the characterization of resistance mechanisms and vulnerabilities.

Purpose of the Study:

  • To investigate the molecular phenotypes and exploitable vulnerabilities in CDK4/6i-resistant breast cancer.
  • To identify potential therapeutic strategies for patients with acquired resistance to CDK4/6i.

Main Methods:

  • Development of CDK4/6i-resistant breast cancer cell lines and patient-derived organoids.
  • Analysis of mitotic fidelity and chromosomal segregation in resistant models.
  • Evaluation of sensitivity to inhibitors of mitotic checkpoint regulators, specifically TTK and Aurora kinase A/B.
  • Assessment of the efficacy of the TTK inhibitor CFI-402257 in resistant models.

Main Results:

  • A subset of CDK4/6i-resistant models exhibited mitotic segregation errors and micronuclei formation.
  • Loss of RB1, a known resistance mechanism, was associated with these mitotic defects.
  • These defects conferred enhanced sensitivity to TTK inhibition.
  • Treatment with CFI-402257 induced premature chromosome segregation, DNA damage, and cell death in sensitive models.

Conclusions:

  • Mitotic defects and sensitivity to TTK inhibition represent a vulnerability in a subset of CDK4/6i-resistant ER+ breast cancers.
  • The TTK inhibitor CFI-402257 shows therapeutic potential for this specific patient population.
  • Targeting mitotic checkpoint regulators offers a promising strategy to overcome CDK4/6i resistance in breast cancer.

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