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Through the Looking Glass: Time-lapse Microscopy and Longitudinal Tracking of Single Cells to Study Anti-cancer Therapeutics
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Weakened APC/C activity at mitotic exit drives cancer vulnerability to KIF18A inhibition

Colin R Gliech1, Zhong Y Yeow1, Daniel Tapias-Gomez1

  • 1Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.

The EMBO Journal
|January 26, 2024
PubMed

Insights

Targeting KIF18A offers a new cancer therapy approach. Inhibiting this motor protein causes mitotic delays, making cancer cells with specific cell division weaknesses vulnerable to treatment.

Area of Science:

  • Cell Biology
  • Cancer Therapeutics
  • Molecular Oncology

Background:

  • Current antimitotic drugs face limitations due to toxicity in healthy tissues.
  • KIF18A, a microtubule motor protein, is a potential cancer therapeutic target due to cancer-specific dependencies.
  • The reasons for varying KIF18A requirement across different cancers are not fully understood.

Purpose of the Study:

  • To investigate the impact of KIF18A inhibition on cancer cell division.
  • To identify the cellular determinants of sensitivity to KIF18A inhibition.
  • To explore KIF18A as a viable therapeutic target by understanding its role in mitotic regulation.

Main Methods:

  • KIF18A inhibition was induced in cancer cells.
  • Spindle assembly checkpoint (SAC) signaling dynamics were analyzed.
  • The metaphase-to-anaphase transition and anaphase-promoting complex/cyclosome (APC/C) activity were assessed.
  • Cellular vulnerabilities related to mitosis were characterized.

Main Results:

  • KIF18A inhibition led to increased SAC signaling and mitotic delays.
  • Cancer cells with weaker APC/C activity or persistent SAC signaling showed heightened sensitivity.
  • KIF18A-dependent cancers displayed hallmarks of SAC:APC/C imbalance, including prolonged metaphase-anaphase transitions.
  • Overall mitosis was slower in sensitive cancer cells.

Conclusions:

  • KIF18A inhibition exploits vulnerabilities in the cancer cell division machinery.
  • The interplay between SAC signaling and APC/C activity dictates sensitivity to KIF18A inhibition.
  • This study reveals a therapeutic strategy targeting specific cell division defects in cancer.
Keywords:
Anaphase Promoting Complex (APC/C)CancerKIF18AMitosisSpindle Assembly Checkpoint (SAC)

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