| First Author | Huang S | Year | 2012 |
| Journal | Cell | Volume | 151 |
| Issue | 5 | Pages | 937-50 |
| PubMed ID | 23178117 | Mgi Jnum | J:196210 |
| Mgi Id | MGI:5487474 | Doi | 10.1016/j.cell.2012.10.035 |
| Citation | Huang S, et al. (2012) MED12 controls the response to multiple cancer drugs through regulation of TGF-beta receptor signaling. Cell 151(5):937-50 |
| abstractText | 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-betaR2 through physical interaction. MED12 suppression therefore results in activation of TGF-betaR signaling, which is both necessary and sufficient for drug resistance. TGF-beta 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-betaR signaling restores drug responsiveness in MED12(KD) cells, suggesting a strategy to treat drug-resistant tumors that have lost MED12. |
