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Updated: Dec 30, 2025
Live Cell Imaging to Assess the Dynamics of Metaphase Timing and Cell Fate Following Mitotic Spindle Perturbations
Published on: September 20, 2019
Altering microtubule dynamics is synergistically toxic with spindle assembly checkpoint inhibition
Klaske M Schukken1, Yu-Chih Lin2, Petra L Bakker1
1European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
Abstract:
Chromosomal instability (CIN) and aneuploidy are hallmarks of cancer. As most cancers are aneuploid, targeting aneuploidy or CIN may be an effective way to target a broad spectrum of cancers. Here, we perform two small molecule compound screens to identify drugs that selectively target cells that are aneuploid or exhibit a CIN phenotype. We find that aneuploid cells are much more sensitive to the energy metabolism regulating drug ZLN005 than their euploid counterparts. Furthermore, cells with an ongoing CIN phenotype, induced by spindle assembly checkpoint (SAC) alleviation, are significantly more sensitive to the Src kinase inhibitor SKI606. We show that inhibiting Src kinase increases microtubule polymerization rates and, more generally, that deregulating microtubule polymerization rates is particularly toxic to cells with a defective SAC. Our findings, therefore, suggest that tumors with a dysfunctional SAC are particularly sensitive to microtubule poisons and, vice versa, that compounds alleviating the SAC provide a powerful means to treat tumors with deregulated microtubule dynamics.
Insights
Aneuploid cancer cells show increased sensitivity to energy metabolism drugs like ZLN005. Cells with chromosomal instability (CIN) are vulnerable to Src kinase inhibitors, suggesting new cancer treatment strategies targeting these vulnerabilities.
Area of Science:
- Oncology
- Cell Biology
- Cancer Genetics
Background:
- Chromosomal instability (CIN) and aneuploidy are common in cancer.
- Targeting these widespread cancer hallmarks offers broad therapeutic potential.
Purpose of the Study:
- To identify drugs selectively targeting aneuploid or CIN cancer cells.
- To explore therapeutic strategies based on cancer cell vulnerabilities.
Main Methods:
- Conducted two small molecule compound screens.
- Assessed drug sensitivity in aneuploid versus euploid cells.
- Investigated drug effects on cells with induced CIN via spindle assembly checkpoint (SAC) alleviation.
Main Results:
- Aneuploid cells are highly sensitive to the energy metabolism drug ZLN005.
- Cells with CIN induced by SAC alleviation are sensitive to the Src kinase inhibitor SKI606.
- Src kinase inhibition enhances microtubule polymerization, proving toxic to cells with defective SAC.
Conclusions:
- Dysfunctional SAC tumors are sensitive to microtubule poisons.
- Compounds alleviating SAC can treat tumors with deregulated microtubule dynamics.
- Targeting energy metabolism and SAC pathways offers novel cancer treatment avenues.
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