MED12 Controls the Response to Multiple Cancer Drugs through Regulation of TGF-

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-

β

R2 through physical interaction. MED12 suppression therefore results in activation of TGF-

β

R 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-

β

R signaling restores drug responsiveness in MED12KD cells, suggesting a strategy to treat drug-resistant tumors that have lost MED12.

º MED12 loss causes resistance to many cancer drugs through enhanced TGF-

β

signaling
º MED12 inhibits TGF-

β

receptor signaling through physical interaction in the cytoplasm
º MED12-regulated genes are predictive for responses to cancer drugs in patients
º MED12-deficient tumors may benefit from therapy that includes a TGF-

β

inhibitor Mutations in a subunit of the Mediator complex, generally thought to be involved in transcription regulation, are a major determinant of resistance to both targeted and chemotherapies in multiple cancers. Surprisingly, MED12 acts in the cytoplasm to repress TGF-

β

signaling; loss of this repression leads to drug resistance.

Cell , résumé, 2011

Voir le bulletin