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Ex vivo screen identifies CDK12 as a metastatic vulnerability in osteosarcoma

ABSTRACT: Despite progress in intensification of therapy, outcomes for patients with metastatic osteosarcoma (OS) have not improved in thirty years. We developed a system that enables preclinical screening of compounds against metastatic OS cells in the context of the native lung microenvironment. Using this strategy to screen a library of epigenetically-targeted compounds, we identified inhibitors of CDK12 to be most effective, reducing OS cell outgrowth in the lung by >90% at sub-micromolar doses. CDK12 inhibition led to defects in transcription elongation in a gene length- and expression-dependent manner. These effects were accompanied by defects in RNA processing and altered the expression of genes involved in transcription regulation and the DNA damage response. We further identify OS models that differ in their sensitivity to CDK12 inhibition in the lung and provide evidence that upregulated MYC levels may mediate these differences. Our studies provide a framework for rapid preclinical testing of compounds with anti-metastatic activity and highlight CDK12 as a potential therapeutic target in osteosarcoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE132233 | GEO | 2019/06/06

REPOSITORIES: GEO

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