Identification of the KIF18A alpha-4 helix as a therapeutic target for chromosomally unstable tumor cells

Area of Science:

• Molecular Biology
• Cell Biology
• Cancer Research

Background:

• KIF18A is a mitotic kinesin crucial for cancer cell proliferation, particularly in tumors with chromosome instability (CIN).
• Targeting KIF18A is a promising strategy for treating aggressive cancers.
• Identifying specific KIF18A regions for inhibition is key for developing effective small molecule drugs.

Purpose of the Study:

• To investigate the role of S284 phosphorylation within the KIF18A alpha-4 helix.
• To determine the impact of S284 mutations on KIF18A function and localization.
• To assess the potential of the KIF18A alpha-4 helix as a therapeutic target.

Main Methods:

• Utilized cultured cell models to study KIF18A function.
• Introduced mutations at the S284 residue within the KIF18A alpha-4 helix.
• Examined KIF18A localization and its effect on proliferation in CIN cells.

Main Results:

• S284 mutations in KIF18A caused its mislocalization from microtubule plus-ends to spindle poles.
• KIF18A S284 mutants lost function and failed to support proliferation in CIN tumor cells.
• KIF18A inhibitors targeting the alpha-4 helix mimicked the effects of S284 mutations on localization and function.

Conclusions:

• The KIF18A alpha-4 helix is a viable target for therapeutic inhibition.
• Small molecules targeting KIF18A selectively inhibit CIN tumor cell proliferation.
• Inhibition of KIF18A by small molecules produces similar mitotic effects as genetic perturbations.