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Ex vivo screen identifies CDK12 as a metastatic vulnerability in osteosarcoma.

The Journal of clinical investigation (2019-09-10)
Ian Bayles, Malgorzata Krajewska, W Dean Pontius, Alina Saiakhova, James J Morrow, Cynthia Bartels, Jim Lu, Zachary J Faber, Yuriy Fedorov, Ellen S Hong, Jaret M Karnuta, Brian Rubin, Drew J Adams, Rani E George, Peter C Scacheri

Despite progress in intensification of therapy, outcomes for patients with metastatic osteosarcoma (OS) have not improved in thirty years. We developed a system that enabled 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 more than 90% at submicromolar doses. We found that knockout of CDK12 in an in vivo model of lung metastasis significantly decreased the ability of OS to colonize the lung. 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 identified OS models that differ in their sensitivity to CDK12 inhibition in the lung and provided evidence that upregulated MYC levels may mediate these differences. Our studies provided a framework for rapid preclinical testing of compounds with antimetastatic activity and highlighted CDK12 as a potential therapeutic target in OS.

Product Number
Product Description

Ribonuclease A from bovine pancreas, for molecular biology, ≥70 Kunitz units/mg protein, lyophilized
Anti-RNA polymerase II subunit B1 (phospho CTD Ser-2) Antibody, clone 3E10, clone 3E10, from rat