title: 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.affiliation: Division of Molecular Carcinogenesis, Cancer Genomics Center and Cancer Systems Biology Center, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Sidong
authors.initials: S
authors.lastname: Huang
authors.forename: Michael
authors.initials: M
authors.lastname: Hölzel
authors.forename: Theo
authors.initials: T
authors.lastname: Knijnenburg
authors.forename: Andreas
authors.initials: A
authors.lastname: Schlicker
authors.forename: Paul
authors.initials: P
authors.lastname: Roepman
authors.forename: Ultan
authors.initials: U
authors.lastname: McDermott
authors.forename: Mathew
authors.initials: M
authors.lastname: Garnett
authors.forename: Wipawadee
authors.initials: W
authors.lastname: Grernrum
authors.forename: Chong
authors.initials: C
authors.lastname: Sun
authors.forename: Anirudh
authors.initials: A
authors.lastname: Prahallad
authors.forename: Floris H
authors.initials: FH
authors.lastname: Groenendijk
authors.forename: Lorenza
authors.initials: L
authors.lastname: Mittempergher
authors.forename: Wouter
authors.initials: W
authors.lastname: Nijkamp
authors.forename: Jacques
authors.initials: J
authors.lastname: Neefjes
authors.forename: Ramon
authors.initials: R
authors.lastname: Salazar
authors.forename: Peter
authors.initials: P
authors.lastname: Ten Dijke
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Uramoto
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Tanaka
authors.forename: Roderick L
authors.initials: RL
authors.lastname: Beijersbergen
authors.forename: Lodewyk F A
authors.initials: LF
authors.lastname: Wessels
authors.forename: René
authors.initials: R
authors.lastname: Bernards
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D020935:MAP Kinase Signaling System; D056892:Mediator Complex / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; C460107:MED12 protein, human; D056892:Mediator Complex; D018125:Receptors, Transforming Growth Factor beta