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Ex vivo screen identifies CDK12 as a metastatic vulnerability in osteosarcoma
Ian Bayles, … , Rani E. George, Peter C. Scacheri
Ian Bayles, … , Rani E. George, Peter C. Scacheri
Published September 9, 2019
Citation Information: J Clin Invest. 2019;129(10):4377-4392. https://doi.org/10.1172/JCI127718.
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Research Article Genetics Oncology

Ex vivo screen identifies CDK12 as a metastatic vulnerability in osteosarcoma

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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 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.

Authors

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

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Figure 6

High levels of MYC correlate with insensitivity of OS cells to E9 treatment ex vivo.

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High levels of MYC correlate with insensitivity of OS cells to E9 treatm...
(A) CNAs in MG63.3 cells (E9 resistant) relative to 143B cells (E9 sensitive) from whole-genome–sequencing data. (B) Cone plot of H3K27ac SE signals across the epigenomes of MG63.3 and 143B cell lines. (C) Browser views of H3K27ac ChIP-Seq signals at the MYC locus. SE identified in each cell line are indicated. (D) MYC transcript levels in MG63.3 and 143B OS cells cultured in vitro as well as at 1 and 14 days in PuMA model. (E) Relative growth of MG63.3 cells in PuMA lung explants after treatment with the indicated compounds compared with control. Data are presented as mean ± SD of triplicate lung sections. *P < 0.05 versus DMSO control by ordinary 1-way ANOVA with Tukey’s multiple comparison testing.
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