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Cell. 2012 Nov 21;151(5):937-50. doi: 10.1016/j.cell.2012.10.035.

MED12 controls the response to multiple cancer drugs through regulation of TGF-β receptor signaling.

Author information

1
Division of Molecular Carcinogenesis, Cancer Genomics Center and Cancer Systems Biology Center, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.

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.

PMID:
23178117
PMCID:
PMC3672971
DOI:
10.1016/j.cell.2012.10.035
[Indexed for MEDLINE]
Free PMC Article

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