Journal
CELL
Volume 151, Issue 5, Pages 937-950Publisher
CELL PRESS
DOI: 10.1016/j.cell.2012.10.035
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Funding
- Dutch Cancer Society
- European Research Council grant
- Cancer Systems Biology Center grant by NWO
- Netherlands Genomics Initiative (NGI)
- Spanish BAE FIS travel grant by Instituto Carlos III
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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-beta R2 through physical interaction. MED12 suppression therefore results in activation of TGF-beta R 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-beta R signaling restores drug responsiveness in MED12(KD) cells, suggesting a strategy to treat drug-resistant tumors that have lost MED12.
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