MED12 controls the response to multiple cancer drugs through regulation of TGF-β receptor signaling.

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.

• Authors: Sidong Huang, Michael Hölzel, Theo Knijnenburg, Andreas Schlicker, Paul Roepman, Ultan McDermott, Mathew Garnett, Wipawadee Grernrum, Chong Sun, Anirudh Prahallad, Floris H Groenendijk, Lorenza Mittempergher, Wouter Nijkamp, Jacques Neefjes, Ramon Salazar, Peter Ten Dijke, Hidetaka Uramoto, Fumihiro Tanaka, Roderick L Beijersbergen, Lodewyk F A Wessels, René Bernards
• Journal: Cell (Cell) Vol. 151 Issue 5 Pg. 937-50 (Nov 21 2012) ISSN: 1097-4172 [Electronic] United States
• PMID: 23178117 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• MED12 protein, human
• Mediator Complex
• Receptors, Transforming Growth Factor beta

Topics

• 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, metabolism)
• Neoplasms (drug therapy)
• Receptors, Transforming Growth Factor beta (metabolism)
• Signal Transduction