Ex vivo screen identifies CDK12 as a metastatic vulnerability in osteosarcoma
Open accessAbstract
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.
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The promising preclinical successes seen with CDK12 inhibitors and drugs that block protein elongation may not be surprising because osteosarcoma cells depend on massive levels of protein production.
“The promising preclinical successes seen with CDK12 inhibitors 92 and drugs that block protein elongation 93 may not be surprising as osteosarcoma cells depend on massive levels of protein production.”
From Osteosarcoma (2022) · cites this paper as [92]
The most intriguing data on cell cycle targets in osteosarcoma have come from a preclinical study of agents that broadly disrupt transcription and translation.
“The most intriguing data have come from a preclinical study of agents that broadly disrupt transcription and translation 92 .”
From Osteosarcoma (2022) · cites this paper as [92]
Well-established cell lines have facilitated investigation into mechanisms of malignancy and high-throughput screens to identify osteosarcoma vulnerabilities.
“Well-established cell lines, such as SaOS, MG63, KHOS, MNNG-HOS, U2OS and OS-17, have facilitated investigation into mechanisms of malignancy 206,207 and high-throughput screens to identify osteosarcoma vulnerabilities 92,208 .”
From Osteosarcoma (2022) · cites this paper as [92]
Ex vivo techniques have been adapted to study tumour-host interactions, screen for metastasis-related vulnerabilities, and validate hits from other screens.
“These techniques have been adapted to study tumour-host interactions, to screen for metastasis-related vulnerabilities and to validate hits identified in other screens 74,75,92,216,217,218,219 .”
From Osteosarcoma (2022) · cites this paper as [92]
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- Authors
- Bayles, I., Krajewska, M., Pontius, W. D., Saiakhova, A., Morrow, J. J., Bartels, C., Lu, J., Faber, Z. J., Fedorov, Y., Hong, E. S., Karnuta, J. M., Rubin, B., Adams, D. J., George, R. E., & Scacheri, P. C.
- Affiliations
- Case Comprehensive Cancer Center (US)
- Boston Children's Hospital (US)
- Cleveland Clinic Lerner College of Medicine (US)
- Cleveland Clinic (US)
- Corresponding author
- Scacheri, Peter C.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2019-09-09
- Volume
- 129
- Issue
- 10
- Pages
- 4377-4392
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC6763270
- OpenAlex
- W2972933432
- Cited by
- 46
- References
- 57
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 9 · 2023: 4 · 2022: 12 · 2021: 3 · 2020: 11
- FWCI
- 4.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5F31CA213965-02, 5R01CA1936,-03, 5R01CA19,336-03)
- National Cancer Institute (5R01CA197336-04)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- osteosarcoma, CDK12, lung metastasis, transcription elongation, RNA processing, epigenetic inhibitors, c-Myc, DNA damage response, therapeutic target
- MeSH terms
- Animals, Drug Screening Assays, Antitumor, Female, Humans, Lung Neoplasms, Osteosarcoma, Mice, SCID, Cyclin-Dependent Kinases, Cell Line, Tumor, Protein Kinase Inhibitors, Mice, Gene Knockout Techniques, Tumor Microenvironment
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