Resistance to BET Bromodomain Inhibitors Is Mediated by Kinome Reprogramming in Ovarian Cancer
Small-molecule BET bromodomain inhibitors (BETis) are actively being pursued in clinical trials for the treatment of a variety of cancers, but the mechanisms of resistance to BETis remain poorly understood. Using a mass spectrometry approach that globally measures kinase signaling at the proteomic l...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2016-08-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124716308609 |
| _version_ | 1819113949238394880 |
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| author | Alison M. Kurimchak Claude Shelton Kelly E. Duncan Katherine J. Johnson Jennifer Brown Shane O’Brien Rashid Gabbasov Lauren S. Fink Yuesheng Li Nicole Lounsbury Magid Abou-Gharbia Wayne E. Childers Denise C. Connolly Jonathan Chernoff Jeffrey R. Peterson James S. Duncan |
| author_facet | Alison M. Kurimchak Claude Shelton Kelly E. Duncan Katherine J. Johnson Jennifer Brown Shane O’Brien Rashid Gabbasov Lauren S. Fink Yuesheng Li Nicole Lounsbury Magid Abou-Gharbia Wayne E. Childers Denise C. Connolly Jonathan Chernoff Jeffrey R. Peterson James S. Duncan |
| author_sort | Alison M. Kurimchak |
| collection | DOAJ |
| description | Small-molecule BET bromodomain inhibitors (BETis) are actively being pursued in clinical trials for the treatment of a variety of cancers, but the mechanisms of resistance to BETis remain poorly understood. Using a mass spectrometry approach that globally measures kinase signaling at the proteomic level, we evaluated the response of the kinome to targeted BETi treatment in a panel of BRD4-dependent ovarian carcinoma (OC) cell lines. Despite initial inhibitory effects of BETi, OC cells acquired resistance following sustained treatment with the BETi JQ1. Through application of multiplexed inhibitor beads (MIBs) and mass spectrometry, we demonstrate that BETi resistance is mediated by adaptive kinome reprogramming, where activation of compensatory pro-survival kinase networks overcomes BET protein inhibition. Furthermore, drug combinations blocking these kinases may prevent or delay the development of drug resistance and enhance the efficacy of BETi therapy. |
| first_indexed | 2024-12-22T04:37:31Z |
| format | Article |
| id | doaj.art-e79692fa8e914be09f6af9dfa3135db9 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-22T04:37:31Z |
| publishDate | 2016-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-e79692fa8e914be09f6af9dfa3135db92022-12-21T18:38:52ZengElsevierCell Reports2211-12472016-08-011651273128610.1016/j.celrep.2016.06.091Resistance to BET Bromodomain Inhibitors Is Mediated by Kinome Reprogramming in Ovarian CancerAlison M. Kurimchak0Claude Shelton1Kelly E. Duncan2Katherine J. Johnson3Jennifer Brown4Shane O’Brien5Rashid Gabbasov6Lauren S. Fink7Yuesheng Li8Nicole Lounsbury9Magid Abou-Gharbia10Wayne E. Childers11Denise C. Connolly12Jonathan Chernoff13Jeffrey R. Peterson14James S. Duncan15Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USACancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USACancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USACancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USACancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USAMolecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USAMolecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USACancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USACancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USAMoulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, PA 19140, USAMoulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, PA 19140, USAMoulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, PA 19140, USAMolecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USACancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USACancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USACancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USASmall-molecule BET bromodomain inhibitors (BETis) are actively being pursued in clinical trials for the treatment of a variety of cancers, but the mechanisms of resistance to BETis remain poorly understood. Using a mass spectrometry approach that globally measures kinase signaling at the proteomic level, we evaluated the response of the kinome to targeted BETi treatment in a panel of BRD4-dependent ovarian carcinoma (OC) cell lines. Despite initial inhibitory effects of BETi, OC cells acquired resistance following sustained treatment with the BETi JQ1. Through application of multiplexed inhibitor beads (MIBs) and mass spectrometry, we demonstrate that BETi resistance is mediated by adaptive kinome reprogramming, where activation of compensatory pro-survival kinase networks overcomes BET protein inhibition. Furthermore, drug combinations blocking these kinases may prevent or delay the development of drug resistance and enhance the efficacy of BETi therapy.http://www.sciencedirect.com/science/article/pii/S2211124716308609 |
| spellingShingle | Alison M. Kurimchak Claude Shelton Kelly E. Duncan Katherine J. Johnson Jennifer Brown Shane O’Brien Rashid Gabbasov Lauren S. Fink Yuesheng Li Nicole Lounsbury Magid Abou-Gharbia Wayne E. Childers Denise C. Connolly Jonathan Chernoff Jeffrey R. Peterson James S. Duncan Resistance to BET Bromodomain Inhibitors Is Mediated by Kinome Reprogramming in Ovarian Cancer Cell Reports |
| title | Resistance to BET Bromodomain Inhibitors Is Mediated by Kinome Reprogramming in Ovarian Cancer |
| title_full | Resistance to BET Bromodomain Inhibitors Is Mediated by Kinome Reprogramming in Ovarian Cancer |
| title_fullStr | Resistance to BET Bromodomain Inhibitors Is Mediated by Kinome Reprogramming in Ovarian Cancer |
| title_full_unstemmed | Resistance to BET Bromodomain Inhibitors Is Mediated by Kinome Reprogramming in Ovarian Cancer |
| title_short | Resistance to BET Bromodomain Inhibitors Is Mediated by Kinome Reprogramming in Ovarian Cancer |
| title_sort | resistance to bet bromodomain inhibitors is mediated by kinome reprogramming in ovarian cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211124716308609 |
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