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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Bibliographic Details
Published in:	Cell Vol. 151; no. 5; p. 937
Main Authors:	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
Language:	English
Published:	United States 21.11.2012
Subjects:	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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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1097-4172 1097-4172
DOI:	10.1016/j.cell.2012.10.035