Author/Authors :
Sidong Huang، نويسنده , , Michael H?lzel، نويسنده , , Theo Knijnenburg، نويسنده , , Andreas Schlicker، نويسنده , , Paul Roepman، نويسنده , , Ultan McDermott، نويسنده , , Mathew Garnett، نويسنده , , Wipawadee Grernrum، نويسنده , , Chong Sun، نويسنده , , Anirudh Prahallad، نويسنده , , Floris H. Groenendijk، نويسنده , , Lorenza Mittempergher، نويسنده , , Wouter Nijkamp، نويسنده , , Jacques Neefjes، نويسنده , , Ramon Salazar، نويسنده , , Peter ten Dijke، نويسنده , , Hidetaka Uramoto، نويسنده , , Fumihiro Tanaka، نويسنده , , Roderick L. Beijersbergen، نويسنده , , Lodewyk F.A. Wessels، نويسنده , , et al.، نويسنده ,
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 MED12KD cells, suggesting a strategy to treat drug-resistant tumors that have lost MED12.
