Targeting chromosomally unstable tumors with a selective KIF18A inhibitor

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Chromosome instability is a common cancer trait but remains therapeutically underexploited.
• Identifying specific vulnerabilities in chromosomally unstable (CIN) cancer cells is crucial for targeted therapies.

Purpose of the Study:

• To identify genes uniquely essential for the survival of CIN cancer cells.
• To develop and validate a targeted therapeutic strategy against CIN cancers.

Main Methods:

• Utilized the Cancer Dependency Map to find genes essential in high copy number aberration tumor cells.
• Validated Kinesin Family Member 18A (KIF18A) as a target through gene knockdown experiments.
• Screened chemical libraries to identify and optimize KIF18A inhibitors, leading to VLS-1272.
• Assessed VLS-1272's efficacy in cancer cell lines and tumor xenografts.

Main Results:

• KIF18A was identified as essential for CIN cancer cells, with its knockdown causing mitotic defects and reduced tumor growth.
• Developed VLS-1272, an orally bioavailable, potent, and selective KIF18A inhibitor.
• VLS-1272 treatment induced chromosome congression defects, mitotic arrest, and cell death.
• VLS-1272 demonstrated specific efficacy against CIN cancer cells and significantly inhibited tumor xenograft growth.

Conclusions:

• KIF18A is a validated therapeutic vulnerability in chromosomally unstable cancers.
• VLS-1272 is a promising KIF18A inhibitor with potential for clinical development.
• Targeting KIF18A offers a novel therapeutic approach for cancers characterized by high chromosomal instability.