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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Veröffentlicht in:Cell Jg. 151; H. 5; S. 937
Hauptverfasser: Huang, Sidong, Hölzel, Michael, Knijnenburg, Theo, Schlicker, Andreas, Roepman, Paul, McDermott, Ultan, Garnett, Mathew, Grernrum, Wipawadee, Sun, Chong, Prahallad, Anirudh, Groenendijk, Floris H, Mittempergher, Lorenza, Nijkamp, Wouter, Neefjes, Jacques, Salazar, Ramon, Ten Dijke, Peter, Uramoto, Hidetaka, Tanaka, Fumihiro, Beijersbergen, Roderick L, Wessels, Lodewyk F A, Bernards, René
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 21.11.2012
Schlagworte:
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
ISSN:1097-4172, 1097-4172
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Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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content type line 23
ISSN:1097-4172
1097-4172
DOI:10.1016/j.cell.2012.10.035