Turn chromosomal chaos into a weakness with KIF18A inhibitors
Highly unstable tumours survive constant chromosome mistakes by leaning on a motor protein. Blocking it kills unstable cancer cells while sparing normal ones.
Chromosomally unstable, often whole-genome-doubled tumours depend on the kinesin KIF18A for mitotic fidelity, whereas diploid cells do not. KIF18A inhibitors are in early trials in ovarian and other CIN-high cancers. The proposal is to use CIN and whole-genome doubling, measured from routine sequencing, as the selection biomarker and to test KIF18A inhibition specifically after platinum resistance, when instability is highest.
- Tumour heterogeneity and clonal evolution · A tumour is many tumours. Treatments that kill most cells leave the rest to grow back, changed.
- The undruggable drivers · The proteins that drive most cancers, such as MYC, mutant p53 and most RAS variants, still have no good drug.
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