KIF18A Maintains Kinetochore-Microtubule Attachments in CIN Cells by Limiting Microtubule Polymerization

Area of Science:

• Cell Biology
• Cancer Biology
• Genetics

Background:

• Chromosomal instability (CIN) is a hallmark of cancer.
• CIN creates vulnerabilities exploitable for cancer therapy, such as sensitivity to KIF18A inhibition.
• The precise mechanisms underlying KIF18A dependency in CIN tumors are not fully understood.

Purpose of the Study:

• To elucidate the mechanistic basis for KIF18A dependency in a subset of CIN tumor cells.
• To compare mitotic phenotypes between KIF18A-sensitive and -insensitive CIN cell models.

Main Methods:

• Comparative analysis of mitotic phenotypes in KIF18A-sensitive and -insensitive cell models.
• Assessment of kinetochore-microtubule attachment stability.
• Evaluation of microtubule polymerization rates and dynamics.
• Investigation of spindle assembly checkpoint (SAC) protein recruitment.

Main Results:

• KIF18A inhibition in sensitive CIN cells causes polar chromosome formation, unattached kinetochores, SAC protein recruitment, and mitotic arrest.
• While KIF18A loss reduces kinetochore-microtubule stability in all cells, sensitive cells have lower baseline stability and higher microtubule polymerization rates.
• KIF18A inhibition disrupts post-alignment attachment maintenance; reducing microtubule polymerization mitigates mitotic defects.

Conclusions:

• CIN tumor cells depend on KIF18A to control excessive microtubule dynamics.
• KIF18A is crucial for maintaining kinetochore-microtubule attachments in sensitive CIN cells.
• This dependency offers a potential therapeutic strategy targeting KIF18A in CIN-driven cancers.