CDK12 Inhibition Reverses De Novo and Acquired PARP Inhibitor Resistance in BRCA Wild-Type and Mutated Models of Triple-Negative Breast Cancer
Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved..
Although poly(ADP-ribose) polymerase (PARP) inhibitors are active in homologous recombination (HR)-deficient cancers, their utility is limited by acquired resistance after restoration of HR. Here, we report that dinaciclib, an inhibitor of cyclin-dependent kinases (CDKs) 1, 2, 5, and 9, additionally has potent activity against CDK12, a transcriptional regulator of HR. In BRCA-mutated triple-negative breast cancer (TNBC) cells and patient-derived xenografts (PDXs), dinaciclib ablates restored HR and reverses PARP inhibitor resistance. Additionally, we show that de novo resistance to PARP inhibition in BRCA1-mutated cell lines and a PDX derived from a PARP-inhibitor-naive BRCA1 carrier is mediated by residual HR and is reversed by CDK12 inhibition. Finally, dinaciclib augments the degree of response in a PARP-inhibitor-sensitive model, converting tumor growth inhibition to durable regression. These results highlight the significance of HR disruption as a therapeutic strategy and support the broad use of combined CDK12 and PARP inhibition in TNBC.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2016 |
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| Erschienen: |
2016 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:17 |
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| Enthalten in: |
Cell reports - 17(2016), 9 vom: 22. Nov., Seite 2367-2381 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Johnson, Shawn F [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 21.11.2017 Date Revised 04.12.2021 published: Print Citation Status MEDLINE |
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| doi: |
10.1016/j.celrep.2016.10.077 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM266500145 |
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| 100 | 1 | |a Johnson, Shawn F |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a CDK12 Inhibition Reverses De Novo and Acquired PARP Inhibitor Resistance in BRCA Wild-Type and Mutated Models of Triple-Negative Breast Cancer |
| 264 | 1 | |c 2016 | |
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| 500 | |a Date Completed 21.11.2017 | ||
| 500 | |a Date Revised 04.12.2021 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a Although poly(ADP-ribose) polymerase (PARP) inhibitors are active in homologous recombination (HR)-deficient cancers, their utility is limited by acquired resistance after restoration of HR. Here, we report that dinaciclib, an inhibitor of cyclin-dependent kinases (CDKs) 1, 2, 5, and 9, additionally has potent activity against CDK12, a transcriptional regulator of HR. In BRCA-mutated triple-negative breast cancer (TNBC) cells and patient-derived xenografts (PDXs), dinaciclib ablates restored HR and reverses PARP inhibitor resistance. Additionally, we show that de novo resistance to PARP inhibition in BRCA1-mutated cell lines and a PDX derived from a PARP-inhibitor-naive BRCA1 carrier is mediated by residual HR and is reversed by CDK12 inhibition. Finally, dinaciclib augments the degree of response in a PARP-inhibitor-sensitive model, converting tumor growth inhibition to durable regression. These results highlight the significance of HR disruption as a therapeutic strategy and support the broad use of combined CDK12 and PARP inhibition in TNBC | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a BRCA-associated breast cancer | |
| 650 | 4 | |a CDK inhibitor | |
| 650 | 4 | |a CDK12 | |
| 650 | 4 | |a PARP inhibitor | |
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| 700 | 1 | |a Greifenberg, Ann Katrin |e verfasserin |4 aut | |
| 700 | 1 | |a Dust, Sofia |e verfasserin |4 aut | |
| 700 | 1 | |a Stover, Daniel G |e verfasserin |4 aut | |
| 700 | 1 | |a Chi, David |e verfasserin |4 aut | |
| 700 | 1 | |a Primack, Benjamin |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, Shiliang |e verfasserin |4 aut | |
| 700 | 1 | |a Bernhardy, Andrea J |e verfasserin |4 aut | |
| 700 | 1 | |a Coulson, Rhiannon |e verfasserin |4 aut | |
| 700 | 1 | |a Lazaro, Jean-Bernard |e verfasserin |4 aut | |
| 700 | 1 | |a Kochupurakkal, Bose |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Heather |e verfasserin |4 aut | |
| 700 | 1 | |a Unitt, Christine |e verfasserin |4 aut | |
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| 700 | 1 | |a Sarosiek, Kristopher A |e verfasserin |4 aut | |
| 700 | 1 | |a Scaltriti, Maurizio |e verfasserin |4 aut | |
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| 700 | 1 | |a Rodig, Scott J |e verfasserin |4 aut | |
| 700 | 1 | |a D'Andrea, Alan D |e verfasserin |4 aut | |
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