Cancer 1-9

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

S. D. Huang, M. Holzel, T. Knijnenburg, A. Schlicker, P. Roepman, U. McDermott, M. Garnett, W. Grernrum, C. Sun, A. Prahallad, et al.

Cell.2012 Nov;151(5):937-950.

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-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.

Times Cited: 6

Keywords: anaplastic lymphoma kinase, cell lung-cancer, colorectal-cancer, resistance, mutations, sensitivity, inhibition, pathway, therapy, screen


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