EWS/FLI Confers Tumor Cell Synthetic Lethality to CDK12 Inhibition in Ewing Sarcoma
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 T...
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Elsevier BV
2019
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| Online Access: | http://hdl.handle.net/1721.1/121107 https://orcid.org/0000-0001-8855-8647 |
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| author | 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. Gray, Nathanael S. Stegmaier, Kimberly Young, Richard A. |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology 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. Gray, Nathanael S. Stegmaier, Kimberly Young, Richard A. |
| author_sort | Iniguez, Amanda Balboni |
| collection | MIT |
| description | 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. Iniguez et al. find that inhibition of CDK12 is synthetic lethal with EWS/FLI expression. CDK12/13 inhibitors impair DNA damage repair in cells expressing EWS/FLI, and the combination of CDK12/13 and PARP inhibitors synergistically reduces tumor growth and extends survival in Ewing sarcoma mouse models. |
| first_indexed | 2024-09-23T08:00:23Z |
| format | Article |
| id | mit-1721.1/121107 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T08:00:23Z |
| publishDate | 2019 |
| publisher | Elsevier BV |
| record_format | dspace |
| spelling | mit-1721.1/1211072022-09-30T01:38:46Z EWS/FLI Confers Tumor Cell Synthetic Lethality to CDK12 Inhibition in Ewing Sarcoma 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. Gray, Nathanael S. Stegmaier, Kimberly Young, Richard A. Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Young, Richard A 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. Iniguez et al. find that inhibition of CDK12 is synthetic lethal with EWS/FLI expression. CDK12/13 inhibitors impair DNA damage repair in cells expressing EWS/FLI, and the combination of CDK12/13 and PARP inhibitors synergistically reduces tumor growth and extends survival in Ewing sarcoma mouse models. 2019-03-26T17:10:19Z 2019-03-26T17:10:19Z 2018-02 2019-03-15T12:42:01Z Article http://purl.org/eprint/type/JournalArticle 15356108 1535-6108 http://hdl.handle.net/1721.1/121107 Iniguez, Amanda Balboni, Björn Stolte, Emily Jue Wang, Amy Saur Conway, Gabriela Alexe, Neekesh V. Dharia, Nicholas Kwiatkowski, et al. “EWS/FLI Confers Tumor Cell Synthetic Lethality to CDK12 Inhibition in Ewing Sarcoma.” Cancer Cell 33, no. 2 (February 2018): 202–216.e6. © 2017 Elsevier Inc. https://orcid.org/0000-0001-8855-8647 http://dx.doi.org/10.1016/J.CCELL.2017.12.009 Cancer Cell Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier BV PMC |
| spellingShingle | 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. Gray, Nathanael S. Stegmaier, Kimberly Young, Richard A. EWS/FLI Confers Tumor Cell Synthetic Lethality to CDK12 Inhibition in Ewing Sarcoma |
| title | EWS/FLI Confers Tumor Cell Synthetic Lethality to CDK12 Inhibition in Ewing Sarcoma |
| title_full | EWS/FLI Confers Tumor Cell Synthetic Lethality to CDK12 Inhibition in Ewing Sarcoma |
| title_fullStr | EWS/FLI Confers Tumor Cell Synthetic Lethality to CDK12 Inhibition in Ewing Sarcoma |
| title_full_unstemmed | EWS/FLI Confers Tumor Cell Synthetic Lethality to CDK12 Inhibition in Ewing Sarcoma |
| title_short | EWS/FLI Confers Tumor Cell Synthetic Lethality to CDK12 Inhibition in Ewing Sarcoma |
| title_sort | ews fli confers tumor cell synthetic lethality to cdk12 inhibition in ewing sarcoma |
| url | http://hdl.handle.net/1721.1/121107 https://orcid.org/0000-0001-8855-8647 |
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