Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML
Occurrence of the BCR-ABL[superscript T315I] gatekeeper mutation is among the most pressing challenges in the therapy of chronic myeloid leukemia (CML). Several BCR-ABL inhibitors have multiple targets and pleiotropic effects that could be exploited for their synergistic potential. Testing combinati...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Nature Publishing Group
2014
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| Online Access: | http://hdl.handle.net/1721.1/89043 https://orcid.org/0000-0002-1545-1651 |
| _version_ | 1811097290267426816 |
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| author | Winter, Georg E Rix, Uwe Gleixner, Karoline V Grebien, Florian Gridling, Manuela Breitwieser, Florian P Bilban, Martin Colinge, Jacques Valent, Peter Bennett, Keiryn L Superti-Furga, Giulio Carlson, Scott M. White, Forest M. Muller, Andre C |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Winter, Georg E Rix, Uwe Gleixner, Karoline V Grebien, Florian Gridling, Manuela Breitwieser, Florian P Bilban, Martin Colinge, Jacques Valent, Peter Bennett, Keiryn L Superti-Furga, Giulio Carlson, Scott M. White, Forest M. Muller, Andre C |
| author_sort | Winter, Georg E |
| collection | MIT |
| description | Occurrence of the BCR-ABL[superscript T315I] gatekeeper mutation is among the most pressing challenges in the therapy of chronic myeloid leukemia (CML). Several BCR-ABL inhibitors have multiple targets and pleiotropic effects that could be exploited for their synergistic potential. Testing combinations of such kinase inhibitors identified a strong synergy between danusertib and bosutinib that exclusively affected CML cells harboring BCR-ABL[superscript T315I]. To elucidate the underlying mechanisms, we applied a systems-level approach comprising phosphoproteomics, transcriptomics and chemical proteomics. Data integration revealed that both compounds targeted Mapk pathways downstream of BCR-ABL, resulting in impaired activity of c-Myc. Using pharmacological validation, we assessed that the relative contributions of danusertib and bosutinib could be mimicked individually by Mapk inhibitors and collectively by downregulation of c-Myc through Brd4 inhibition. Thus, integration of genome- and proteome-wide technologies enabled the elucidation of the mechanism by which a new drug synergy targets the dependency of BCR-ABL[superscript T315I] CML cells on c-Myc through nonobvious off targets. |
| first_indexed | 2024-09-23T16:57:19Z |
| format | Article |
| id | mit-1721.1/89043 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T16:57:19Z |
| publishDate | 2014 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/890432022-09-29T22:37:12Z Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML Winter, Georg E Rix, Uwe Gleixner, Karoline V Grebien, Florian Gridling, Manuela Breitwieser, Florian P Bilban, Martin Colinge, Jacques Valent, Peter Bennett, Keiryn L Superti-Furga, Giulio Carlson, Scott M. White, Forest M. Muller, Andre C Massachusetts Institute of Technology. Department of Biological Engineering Koch Institute for Integrative Cancer Research at MIT Carlson, Scott M. White, Forest M. Occurrence of the BCR-ABL[superscript T315I] gatekeeper mutation is among the most pressing challenges in the therapy of chronic myeloid leukemia (CML). Several BCR-ABL inhibitors have multiple targets and pleiotropic effects that could be exploited for their synergistic potential. Testing combinations of such kinase inhibitors identified a strong synergy between danusertib and bosutinib that exclusively affected CML cells harboring BCR-ABL[superscript T315I]. To elucidate the underlying mechanisms, we applied a systems-level approach comprising phosphoproteomics, transcriptomics and chemical proteomics. Data integration revealed that both compounds targeted Mapk pathways downstream of BCR-ABL, resulting in impaired activity of c-Myc. Using pharmacological validation, we assessed that the relative contributions of danusertib and bosutinib could be mimicked individually by Mapk inhibitors and collectively by downregulation of c-Myc through Brd4 inhibition. Thus, integration of genome- and proteome-wide technologies enabled the elucidation of the mechanism by which a new drug synergy targets the dependency of BCR-ABL[superscript T315I] CML cells on c-Myc through nonobvious off targets. 2014-08-26T12:05:55Z 2014-08-26T12:05:55Z 2012-09 2012-06 Article http://purl.org/eprint/type/JournalArticle 1552-4450 1552-4469 http://hdl.handle.net/1721.1/89043 Winter, Georg E, Uwe Rix, Scott M Carlson, Karoline V Gleixner, Florian Grebien, Manuela Gridling, Andre C Muller, et al. “Systems-Pharmacology Dissection of a Drug Synergy in Imatinib-Resistant CML.” Nat Chem Biol 8, no. 11 (September 30, 2012): 905–912. https://orcid.org/0000-0002-1545-1651 en_US http://dx.doi.org/10.1038/nchembio.1085 Nature Chemical Biology 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 Nature Publishing Group PMC |
| spellingShingle | Winter, Georg E Rix, Uwe Gleixner, Karoline V Grebien, Florian Gridling, Manuela Breitwieser, Florian P Bilban, Martin Colinge, Jacques Valent, Peter Bennett, Keiryn L Superti-Furga, Giulio Carlson, Scott M. White, Forest M. Muller, Andre C Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML |
| title | Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML |
| title_full | Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML |
| title_fullStr | Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML |
| title_full_unstemmed | Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML |
| title_short | Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML |
| title_sort | systems pharmacology dissection of a drug synergy in imatinib resistant cml |
| url | http://hdl.handle.net/1721.1/89043 https://orcid.org/0000-0002-1545-1651 |
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