Cited by 186Sarcoma Diagnosis and TreatmentPARP inhibition in cancer therapyChromatin Remodeling and Cancer

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EWS/FLI Confers Tumor Cell Synthetic Lethality to CDK12 Inhibition in Ewing Sarcoma

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Iniguez, Amanda Balboni, Stolte, Björn, Wang, Emily Jue, Conway, Amy Saur, Alexe, Gabriela, Dharia, Neekesh V., Kwiatkowski, Nicholas, Zhang, Tinghu, Abraham, Brian J., Mora, Jaume, Kalev, Peter, Leggett, Alan, Chowdhury, Dipanjan, Benes, Cyril H., Young, Richard A., Gray, Nathanael S., Stegmaier, Kimberly·2018·Cancer Cell

DOI 10.1016/j.ccell.2017.12.009PMC PMC5846483

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Abstract

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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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: Iniguez, Amanda Balboni
Conway, Amy Saur
Alexe, Gabriela
Dharia, Neekesh V.
Kwiatkowski, Nicholas
Zhang, Tinghu
Abraham, Brian J.
Mora, Jaume
Chowdhury, Dipanjan
Benes, Cyril H.
Young, Richard A.
Gray, Nathanael S.
Stegmaier, Kimberly
Venue: Cancer Cell
Publisher: Elsevier BV
Published: 2018-02
Volume: 33
Issue: 2
Pages: 202-216.e6
ISSN: 1535-6108 (ISSN-L)
DOI: 10.1016/j.ccell.2017.12.009
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: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 376 d)
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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EWS/FLI Confers Tumor Cell Synthetic Lethality to CDK12 Inhibition in Ewing Sarcoma

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