{"entity":{"id":"idea-targeting-aneuploidy","kind":"idea","name":"Is aneuploidy itself a druggable vulnerability?","aka":[],"tldr":"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).","asOf":"2026-09-08","links":[{"label":"Ben-David and Amon, Context is everything: aneuploidy in cancer (Nature Reviews Genetics 2019)","url":"https://doi.org/10.1038/s41576-019-0171-x"}],"tags":["mechanism","open-question"],"related":[],"cancers":["ovarian","tnbc"],"sections":[],"technologies":[],"targets":["tp53"],"drugs":[],"companies":[],"institutions":["francis-crick","mskcc","stanford"],"pathways":["chromosomal-instability","cgas-sting"],"terms":["whole-genome-doubling"],"trials":["nct03268382"],"people":[],"bottlenecks":[],"keyPapers":["paper-vogelstein-surfing-p53-network-nature-2000","paper-ben-david-nat-rev-genet"],"journals":[],"dependsOn":[],"notes":[],"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.","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"},"route":"/ideas/idea-targeting-aneuploidy/","neighbours":{"cancer":[{"id":"ovarian","kind":"cancer","name":"Ovarian cancer","route":"/cancers/ovarian/"},{"id":"tnbc","kind":"cancer","name":"Triple-negative breast cancer (TNBC)","route":"/cancers/tnbc/"}],"target":[{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"institution":[{"id":"mskcc","kind":"institution","name":"Memorial Sloan Kettering Cancer Center","route":"/institutions/mskcc/"},{"id":"stanford","kind":"institution","name":"Stanford Health Care / Stanford Cancer Institute","route":"/institutions/stanford/"},{"id":"francis-crick","kind":"institution","name":"The Francis Crick Institute","route":"/institutions/francis-crick/"}],"pathway":[{"id":"cgas-sting","kind":"pathway","name":"cGAS-STING innate sensing","route":"/pathways/cgas-sting/"},{"id":"chromosomal-instability","kind":"pathway","name":"Chromosomal instability & aneuploidy","route":"/pathways/chromosomal-instability/"}],"term":[{"id":"whole-genome-doubling","kind":"term","name":"Whole-genome doubling (WGD)","route":"/terms/whole-genome-doubling/"}],"trial":[{"id":"nct03268382","kind":"trial","name":"p53 Activation in Platinum-Resistant High Grade Serous Ovarian Cancer, a Study of PLD With APR-246","route":"/trials/nct03268382/"}],"paper":[{"id":"paper-ben-david-nat-rev-genet","kind":"paper","name":"Context is everything: aneuploidy in cancer","route":"/key-papers/paper-ben-david-nat-rev-genet/"},{"id":"paper-vogelstein-surfing-p53-network-nature-2000","kind":"paper","name":"Vogelstein, Lane and Levine 2000: surfing the p53 network","route":"/key-papers/paper-vogelstein-surfing-p53-network-nature-2000/"}]}}