# Turn chromosomal chaos into a weakness with KIF18A inhibitors

Source: https://onco.cc/ideas/idea-bio1-cin-vulnerability-kif18a/  
OnCo record `idea-bio1-cin-vulnerability-kif18a` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Chromosomally unstable, often whole-genome-doubled tumours survive constant chromosome mistakes by depending on the motor protein KIF18A, which diploid cells do not need. Blocking it kills unstable cancer cells while sparing normal ones; inhibitors are in early trials in ovarian and other cancers.

## Summary

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.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- Hypothesis: KIF18A inhibition produces objective responses predominantly in tumours with high CIN scores and whole-genome doubling, and CIN score outperforms histology as the selection criterion.
- Rationale: Synthetic lethality with CIN was identified in CRISPR screens; heterogeneity-generating instability is thereby converted from the tumour's advantage into a targetable dependency.
- Proposed test: Biomarker-enriched phase 2 in platinum-resistant high-grade serous ovarian and TNBC with pre-specified CIN-high and CIN-low strata; compare response rates.
- Maturity: early-clinical
- Actor: industry

## Sources

- Bottleneck evidence (Tumour heterogeneity and clonal evolution): Gerlinger et al., Intratumor heterogeneity and branched evolution (NEJM 2012): https://doi.org/10.1056/NEJMoa1113205

## Connected records

- cancers: [Ovarian cancer](https://onco.cc/cancers/ovarian/), [Triple-negative breast cancer (TNBC)](https://onco.cc/cancers/tnbc/)
- technologies: [CRISPR functional genomics](https://onco.cc/technologies/crispr-screens/), [Synthetic lethality approaches](https://onco.cc/technologies/synthetic-lethality-approaches/)
- companies: [Amgen](https://onco.cc/companies/amgen/)
- terms: [Synthetic lethality](https://onco.cc/terms/synthetic-lethality/)
- bottlenecks: [The undruggable drivers](https://onco.cc/bottlenecks/b-undruggable-targets/), [Tumour heterogeneity and clonal evolution](https://onco.cc/bottlenecks/b-tumor-heterogeneity/)

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