# Is aneuploidy itself a druggable vulnerability?

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

## TL;DR

Most cancers have the wrong number of chromosomes; normal cells do not. If that difference creates a specific weakness, a drug against it would spare normal tissue by definition.

## Summary

This open question asks whether aneuploidy itself is a druggable vulnerability: most cancers have the wrong number of chromosomes and normal cells do not, so a drug against that difference would spare normal tissue. CIN cells depend on KIF18A, the spindle checkpoint, BCL-XL and proteostasis, and KIF18A inhibitors (sovilnesib, AMG 650) showed activity in platinum-resistant Ovarian cancer in 2024-25. The hypothesis is that a CIN score selects patients whose tumours regress on KIF18A or spindle-checkpoint therapy, and that STING modulators (cGAS-STING pathway) add immunity. The test is a randomised phase 2 of a KIF18A inhibitor against chemotherapy in CIN-high, TP53-mutant ovarian cancer; see also Whole-genome doubling (WGD).

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- Tags: mechanism; open-question
- Hypothesis: A CIN score (from WGS or a FISH panel) selects patients whose tumours regress on KIF18A or SAC-directed therapy, and combination with STING-modulating agents converts CIN's immune tolerance into immunity.
- Rationale: Sheltzer and Bakhoum lab data; the eDyNAmiC and TRACERx programmes provide biomarkers; early clinical responses in CIN-high ovarian cancer.
- Proposed test: Randomised phase 2 of a KIF18A inhibitor vs chemotherapy in CIN-high, TP53-mutant platinum-resistant ovarian cancer, with CIN score stratification and micronuclei/STING pharmacodynamics.
- Maturity: early-clinical

## Sources

- Ben-David and Amon, Context is everything: aneuploidy in cancer (Nature Reviews Genetics 2019): https://doi.org/10.1038/s41576-019-0171-x

## Connected records

- cancers: [Ovarian cancer](https://onco.cc/cancers/ovarian/), [Triple-negative breast cancer (TNBC)](https://onco.cc/cancers/tnbc/)
- targets: [TP53](https://onco.cc/targets/tp53/)
- institutions: [Memorial Sloan Kettering Cancer Center](https://onco.cc/institutions/mskcc/), [Stanford Health Care / Stanford Cancer Institute](https://onco.cc/institutions/stanford/), [The Francis Crick Institute](https://onco.cc/institutions/francis-crick/)
- pathways: [cGAS-STING innate sensing](https://onco.cc/pathways/cgas-sting/), [Chromosomal instability & aneuploidy](https://onco.cc/pathways/chromosomal-instability/)
- terms: [Whole-genome doubling (WGD)](https://onco.cc/terms/whole-genome-doubling/)
- trials: [p53 Activation in Platinum-Resistant High Grade Serous Ovarian Cancer, a Study of PLD With APR-246](https://onco.cc/trials/nct03268382/)
- key papers: [Context is everything: aneuploidy in cancer](https://onco.cc/key-papers/paper-ben-david-nat-rev-genet/), [Vogelstein, Lane and Levine 2000: surfing the p53 network](https://onco.cc/key-papers/paper-vogelstein-surfing-p53-network-nature-2000/)

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