MED12 controls the response to multiple cancer drugs through regulation of TGF-β receptor signaling
Inhibitors of the ALK and EGF receptor tyrosine kinases provoke dramatic but short-lived responses in lung cancers harboring EML4-ALK translocations or activating mutations of EGFR, respectively. We used a large-scale RNAi screen to identify MED12, a component of the transcriptional MEDIATOR complex...
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| Vydané v: | Cell Ročník 151; číslo 5; s. 937 |
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| Hlavní autori: | , , , , , , , , , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | English |
| Vydavateľské údaje: |
United States
21.11.2012
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| Predmet: | |
| ISSN: | 1097-4172, 1097-4172 |
| On-line prístup: | Zistit podrobnosti o prístupe |
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| Abstract | Inhibitors of the ALK and EGF receptor tyrosine kinases provoke dramatic but short-lived responses in lung cancers harboring EML4-ALK translocations or activating mutations of EGFR, respectively. We used a large-scale RNAi screen to identify MED12, a component of the transcriptional MEDIATOR complex that is mutated in cancers, as a determinant of response to ALK and EGFR inhibitors. MED12 is in part cytoplasmic where it negatively regulates TGF-βR2 through physical interaction. MED12 suppression therefore results in activation of TGF-βR signaling, which is both necessary and sufficient for drug resistance. TGF-β signaling causes MEK/ERK activation, and consequently MED12 suppression also confers resistance to MEK and BRAF inhibitors in other cancers. MED12 loss induces an EMT-like phenotype, which is associated with chemotherapy resistance in colon cancer patients and to gefitinib in lung cancer. Inhibition of TGF-βR signaling restores drug responsiveness in MED12(KD) cells, suggesting a strategy to treat drug-resistant tumors that have lost MED12. |
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| AbstractList | Inhibitors of the ALK and EGF receptor tyrosine kinases provoke dramatic but short-lived responses in lung cancers harboring EML4-ALK translocations or activating mutations of EGFR, respectively. We used a large-scale RNAi screen to identify MED12, a component of the transcriptional MEDIATOR complex that is mutated in cancers, as a determinant of response to ALK and EGFR inhibitors. MED12 is in part cytoplasmic where it negatively regulates TGF-βR2 through physical interaction. MED12 suppression therefore results in activation of TGF-βR signaling, which is both necessary and sufficient for drug resistance. TGF-β signaling causes MEK/ERK activation, and consequently MED12 suppression also confers resistance to MEK and BRAF inhibitors in other cancers. MED12 loss induces an EMT-like phenotype, which is associated with chemotherapy resistance in colon cancer patients and to gefitinib in lung cancer. Inhibition of TGF-βR signaling restores drug responsiveness in MED12(KD) cells, suggesting a strategy to treat drug-resistant tumors that have lost MED12.Inhibitors of the ALK and EGF receptor tyrosine kinases provoke dramatic but short-lived responses in lung cancers harboring EML4-ALK translocations or activating mutations of EGFR, respectively. We used a large-scale RNAi screen to identify MED12, a component of the transcriptional MEDIATOR complex that is mutated in cancers, as a determinant of response to ALK and EGFR inhibitors. MED12 is in part cytoplasmic where it negatively regulates TGF-βR2 through physical interaction. MED12 suppression therefore results in activation of TGF-βR signaling, which is both necessary and sufficient for drug resistance. TGF-β signaling causes MEK/ERK activation, and consequently MED12 suppression also confers resistance to MEK and BRAF inhibitors in other cancers. MED12 loss induces an EMT-like phenotype, which is associated with chemotherapy resistance in colon cancer patients and to gefitinib in lung cancer. Inhibition of TGF-βR signaling restores drug responsiveness in MED12(KD) cells, suggesting a strategy to treat drug-resistant tumors that have lost MED12. Inhibitors of the ALK and EGF receptor tyrosine kinases provoke dramatic but short-lived responses in lung cancers harboring EML4-ALK translocations or activating mutations of EGFR, respectively. We used a large-scale RNAi screen to identify MED12, a component of the transcriptional MEDIATOR complex that is mutated in cancers, as a determinant of response to ALK and EGFR inhibitors. MED12 is in part cytoplasmic where it negatively regulates TGF-βR2 through physical interaction. MED12 suppression therefore results in activation of TGF-βR signaling, which is both necessary and sufficient for drug resistance. TGF-β signaling causes MEK/ERK activation, and consequently MED12 suppression also confers resistance to MEK and BRAF inhibitors in other cancers. MED12 loss induces an EMT-like phenotype, which is associated with chemotherapy resistance in colon cancer patients and to gefitinib in lung cancer. Inhibition of TGF-βR signaling restores drug responsiveness in MED12(KD) cells, suggesting a strategy to treat drug-resistant tumors that have lost MED12. |
| Author | Hölzel, Michael Sun, Chong Huang, Sidong Neefjes, Jacques Ten Dijke, Peter Groenendijk, Floris H Bernards, René Wessels, Lodewyk F A Knijnenburg, Theo Nijkamp, Wouter Schlicker, Andreas Roepman, Paul McDermott, Ultan Salazar, Ramon Tanaka, Fumihiro Grernrum, Wipawadee Prahallad, Anirudh Uramoto, Hidetaka Garnett, Mathew Mittempergher, Lorenza Beijersbergen, Roderick L |
| Author_xml | – sequence: 1 givenname: Sidong surname: Huang fullname: Huang, Sidong organization: Division of Molecular Carcinogenesis, Cancer Genomics Center and Cancer Systems Biology Center, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands – sequence: 2 givenname: Michael surname: Hölzel fullname: Hölzel, Michael – sequence: 3 givenname: Theo surname: Knijnenburg fullname: Knijnenburg, Theo – sequence: 4 givenname: Andreas surname: Schlicker fullname: Schlicker, Andreas – sequence: 5 givenname: Paul surname: Roepman fullname: Roepman, Paul – sequence: 6 givenname: Ultan surname: McDermott fullname: McDermott, Ultan – sequence: 7 givenname: Mathew surname: Garnett fullname: Garnett, Mathew – sequence: 8 givenname: Wipawadee surname: Grernrum fullname: Grernrum, Wipawadee – sequence: 9 givenname: Chong surname: Sun fullname: Sun, Chong – sequence: 10 givenname: Anirudh surname: Prahallad fullname: Prahallad, Anirudh – sequence: 11 givenname: Floris H surname: Groenendijk fullname: Groenendijk, Floris H – sequence: 12 givenname: Lorenza surname: Mittempergher fullname: Mittempergher, Lorenza – sequence: 13 givenname: Wouter surname: Nijkamp fullname: Nijkamp, Wouter – sequence: 14 givenname: Jacques surname: Neefjes fullname: Neefjes, Jacques – sequence: 15 givenname: Ramon surname: Salazar fullname: Salazar, Ramon – sequence: 16 givenname: Peter surname: Ten Dijke fullname: Ten Dijke, Peter – sequence: 17 givenname: Hidetaka surname: Uramoto fullname: Uramoto, Hidetaka – sequence: 18 givenname: Fumihiro surname: Tanaka fullname: Tanaka, Fumihiro – sequence: 19 givenname: Roderick L surname: Beijersbergen fullname: Beijersbergen, Roderick L – sequence: 20 givenname: Lodewyk F A surname: Wessels fullname: Wessels, Lodewyk F A – sequence: 21 givenname: René surname: Bernards fullname: Bernards, René |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/23178117$$D View this record in MEDLINE/PubMed |
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| Copyright | Copyright © 2012 Elsevier Inc. All rights reserved. |
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| DOI | 10.1016/j.cell.2012.10.035 |
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| References | 23178113 - Cell. 2012 Nov 21;151(5):927-9. doi: 10.1016/j.cell.2012.11.003. 23222482 - Nat Rev Cancer. 2013 Jan;13(1):6-7. doi: 10.1038/nrc3423. |
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| Snippet | Inhibitors of the ALK and EGF receptor tyrosine kinases provoke dramatic but short-lived responses in lung cancers harboring EML4-ALK translocations or... |
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| SubjectTerms | Antineoplastic Agents - therapeutic use Carcinoma, Non-Small-Cell Lung - drug therapy Drug Resistance, Neoplasm Epithelial-Mesenchymal Transition Humans Lung Neoplasms - drug therapy MAP Kinase Signaling System Mediator Complex - genetics Mediator Complex - metabolism Neoplasms - drug therapy Receptors, Transforming Growth Factor beta - metabolism Signal Transduction |
| Title | MED12 controls the response to multiple cancer drugs through regulation of TGF-β receptor signaling |
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