The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.
- MeSH
- buněčné klony účinky léků metabolismus patologie MeSH
- cílená molekulární terapie metody MeSH
- Drosophila melanogaster cytologie genetika MeSH
- genom lidský genetika MeSH
- kraniospinální iradiace MeSH
- lidé MeSH
- lokální recidiva nádoru genetika patologie terapie MeSH
- meduloblastom genetika patologie radioterapie chirurgie terapie MeSH
- modely nemocí na zvířatech MeSH
- mutační analýza DNA MeSH
- myši MeSH
- nádory mozečku genetika patologie radioterapie chirurgie terapie MeSH
- radioterapie řízená obrazem MeSH
- selekce (genetika) účinky léků MeSH
- signální transdukce MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
