Defining principles of combination drug mechanisms of action
Combination chemotherapies have been a mainstay in the treatment of disseminated malignancies for almost 60 y, yet even successful regimens fail to cure many patients. Although their single-drug components are well studied, the mechanisms by which drugs work together in clinical combination regimens...
| Main Authors: | , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | en_US |
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National Academy of Sciences (U.S.)
2013
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| Online Access: | http://hdl.handle.net/1721.1/79755 https://orcid.org/0000-0003-3383-0118 |
| _version_ | 1811097528104386560 |
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| author | Bruno, Peter Michael Gilbert, Luke Andrew Capron, Kelsey L. Hemann, Michael Pritchard, Justin R. Lauffenburger, Douglas A |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Bruno, Peter Michael Gilbert, Luke Andrew Capron, Kelsey L. Hemann, Michael Pritchard, Justin R. Lauffenburger, Douglas A |
| author_sort | Bruno, Peter Michael |
| collection | MIT |
| description | Combination chemotherapies have been a mainstay in the treatment of disseminated malignancies for almost 60 y, yet even successful regimens fail to cure many patients. Although their single-drug components are well studied, the mechanisms by which drugs work together in clinical combination regimens are poorly understood. Here, we combine RNAi-based functional signatures with complementary informatics tools to examine drug combinations. This approach seeks to bring to combination therapy what the knowledge of biochemical targets has brought to single-drug therapy and creates a statistical and experimental definition of “combination drug mechanisms of action.” We show that certain synergistic drug combinations may act as a more potent version of a single drug. Conversely, unlike these highly synergistic combinations, most drugs average extant single-drug variations in therapeutic response. When combined to form multidrug regimens, averaging combinations form averaging regimens that homogenize genetic variation in mouse models of cancer and in clinical genomics datasets. We suggest surprisingly simple and predictable combination mechanisms of action that are independent of biochemical mechanism and have implications for biomarker discovery as well as for the development of regimens with defined genetic dependencies. |
| first_indexed | 2024-09-23T17:00:30Z |
| format | Article |
| id | mit-1721.1/79755 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T17:00:30Z |
| publishDate | 2013 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/797552022-09-29T23:03:29Z Defining principles of combination drug mechanisms of action Bruno, Peter Michael Gilbert, Luke Andrew Capron, Kelsey L. Hemann, Michael Pritchard, Justin R. Lauffenburger, Douglas A Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Pritchard, Justin Robert Bruno, Peter Michael Gilbert, Luke Andrew Capron, Kelsey L. Lauffenburger, Douglas A. Hemann, Michael Combination chemotherapies have been a mainstay in the treatment of disseminated malignancies for almost 60 y, yet even successful regimens fail to cure many patients. Although their single-drug components are well studied, the mechanisms by which drugs work together in clinical combination regimens are poorly understood. Here, we combine RNAi-based functional signatures with complementary informatics tools to examine drug combinations. This approach seeks to bring to combination therapy what the knowledge of biochemical targets has brought to single-drug therapy and creates a statistical and experimental definition of “combination drug mechanisms of action.” We show that certain synergistic drug combinations may act as a more potent version of a single drug. Conversely, unlike these highly synergistic combinations, most drugs average extant single-drug variations in therapeutic response. When combined to form multidrug regimens, averaging combinations form averaging regimens that homogenize genetic variation in mouse models of cancer and in clinical genomics datasets. We suggest surprisingly simple and predictable combination mechanisms of action that are independent of biochemical mechanism and have implications for biomarker discovery as well as for the development of regimens with defined genetic dependencies. National Institutes of Health (U.S.) (Grant R01-CA128803-04) Poitras Foundation (Fellowship for Biomedical Engineering) Virginia and Daniel K. Ludwig Graduate Fellowship National Cancer Institute (U.S.). Integrative Cancer Biology Program (Grant U54-CA112967-0) National Cancer Institute (U.S.). Integrative Cancer Biology Program (Summer Research Fellowship) 2013-08-01T13:52:45Z 2013-08-01T13:52:45Z 2012-12 2012-06 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/79755 Pritchard, J. R., P. M. Bruno, L. A. Gilbert, K. L. Capron, D. A. Lauffenburger, and M. T. Hemann. “PNAS Plus: Defining principles of combination drug mechanisms of action.” Proceedings of the National Academy of Sciences 110, no. 2 (January 8, 2013): E170-E179. https://orcid.org/0000-0003-3383-0118 en_US http://dx.doi.org/10.1073/pnas.1210419110 Proceedings of the National Academy of Sciences Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf National Academy of Sciences (U.S.) PNAS |
| spellingShingle | Bruno, Peter Michael Gilbert, Luke Andrew Capron, Kelsey L. Hemann, Michael Pritchard, Justin R. Lauffenburger, Douglas A Defining principles of combination drug mechanisms of action |
| title | Defining principles of combination drug mechanisms of action |
| title_full | Defining principles of combination drug mechanisms of action |
| title_fullStr | Defining principles of combination drug mechanisms of action |
| title_full_unstemmed | Defining principles of combination drug mechanisms of action |
| title_short | Defining principles of combination drug mechanisms of action |
| title_sort | defining principles of combination drug mechanisms of action |
| url | http://hdl.handle.net/1721.1/79755 https://orcid.org/0000-0003-3383-0118 |
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