{"entity":{"id":"idea-bio1-cin-vulnerability-kif18a","kind":"idea","name":"Turn chromosomal chaos into a weakness with KIF18A inhibitors","aka":[],"tldr":"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.","asOf":"2026-09-08","links":[{"label":"Bottleneck evidence (Tumour heterogeneity and clonal evolution): Gerlinger et al., Intratumor heterogeneity and branched evolution (NEJM 2012)","url":"https://doi.org/10.1056/NEJMoa1113205"}],"tags":[],"related":[],"cancers":["ovarian","tnbc"],"sections":[],"technologies":["synthetic-lethality-approaches","crispr-screens"],"targets":[],"drugs":[],"companies":["amgen"],"institutions":[],"pathways":[],"terms":["synthetic-lethality"],"trials":[],"people":[],"bottlenecks":["b-tumor-heterogeneity","b-undruggable-targets"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"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.","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","cost":"medium","horizonYears":3},"route":"/ideas/idea-bio1-cin-vulnerability-kif18a/","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/"}],"technology":[{"id":"crispr-screens","kind":"technology","name":"CRISPR functional genomics","route":"/technologies/crispr-screens/"},{"id":"synthetic-lethality-approaches","kind":"technology","name":"Synthetic lethality approaches","route":"/technologies/synthetic-lethality-approaches/"}],"company":[{"id":"amgen","kind":"company","name":"Amgen","route":"/companies/amgen/"}],"term":[{"id":"synthetic-lethality","kind":"term","name":"Synthetic lethality","route":"/terms/synthetic-lethality/"}],"bottleneck":[{"id":"b-undruggable-targets","kind":"bottleneck","name":"The undruggable drivers","route":"/bottlenecks/b-undruggable-targets/"},{"id":"b-tumor-heterogeneity","kind":"bottleneck","name":"Tumour heterogeneity and clonal evolution","route":"/bottlenecks/b-tumor-heterogeneity/"}]}}