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EWS/FLI Confers Tumor Cell Synthetic Lethality to CDK12 Inhibition in Ewing Sarcoma
Open accessAbstract
Many cancer types are driven by oncogenic transcription factors that have been difficult to drug. Transcriptional inhibitors, however, may offer inroads into targeting these cancers. Through chemical genomics screening, we identified that Ewing sarcoma is a disease with preferential sensitivity to THZ1, a covalent small-molecule CDK7/12/13 inhibitor. The selective CDK12/13 inhibitor, THZ531, impairs DNA damage repair in an EWS/FLI-dependent manner, supporting a synthetic lethal relationship between response to THZ1/THZ531 and EWS/FLI expression. The combination of these molecules with PARP inhibitors showed striking synergy in cell viability and DNA damage assays in vitro and in multiple models of Ewing sarcoma, including a PDX, in vivo without hematopoietic toxicity.
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“Several studies have shown that inhibiting CDK12 can sensitize cancer cells to PARP inhibitors (Bajrami et al., 2014; Iniguez et al., 2018; Johnson et al., 2016).”
From Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation (2020) · cites this paper as Iniguez et al., 2018
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“Although CDK12 has only recently emerged as a potential vulnerability for different cancer types including Ewing sarcoma, triple-negative breast cancer, and hepatocellular carcinoma (Iniguez et al., 2018;Quereda et al., 2019;Wang et al., 2020)”
From Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer (2021) · cites this paper as Iniguez et al., 2018
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Metadata
- Authors
- Iniguez, A. B., Stolte, B., Wang, E. J., Conway, A. S., Alexe, G., Dharia, N. V., Kwiatkowski, N., Zhang, T., Abraham, B. J., Mora, J., Kalev, P., Leggett, A., Chowdhury, D., Benes, C. H., Young, R. A., Gray, N. S., & Stegmaier, K.
- Affiliations
- Broad Institute (US)
- Boston Children's Hospital (US)
- Harvard University (US)
- Whitehead Institute for Biomedical Research (US)
- Hospital Sant Joan de Déu Barcelona (ES)
- Massachusetts General Hospital (US)
- Corresponding author
- Stegmaier, Kimberly
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 33
- Issue
- 2
- Pages
- 202-216.e6
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC5846483
- OpenAlex
- W2784382470
- Cited by
- 173
- References
- 43
- Citations by year
- 2026: 18 · 2025: 16 · 2024: 25 · 2023: 20 · 2022: 22 · 2021: 24 · 2020: 25 · 2019: 15 · 2018: 8
- FWCI
- 13.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- Funders
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
- National Institutes of Health (HG002668)
- National Cancer Institute (1R35 CA210030)
- St. Baldrick's Foundation
- Dana-Farber/Harvard Cancer Center
- Topics
- Health Sciences › Medicine › Oncology › Sarcoma Diagnosis and Treatment
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- Ewing sarcoma, THZ1, synthetic lethality, DNA repair, PARP inhibitors, combination therapy, transcription inhibitors, patient-derived xenografts
- MeSH terms
- Synthetic Lethal Mutations, Humans, Phenylenediamines, Pyrimidines, Sarcoma, Ewing, Oncogene Proteins, Fusion, Gene Expression Regulation, Neoplastic, Cyclin-Dependent Kinases, RNA-Binding Protein EWS, Cell Line, Tumor, Cell Proliferation, Proto-Oncogene Protein c-fli-1
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