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Response to Multiple Cancer Drugs through Regulation of TGF-β Receptor Signaling: a MED12 Control

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, tagged , , , , , , , on November 21, 2012| 4 Comments »

Reporter: Aviva Lev-Ari, PhD, RN

 

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

Cell, Volume 151, Issue 5, 937-950, 21 November 2012
Copyright © 2012 Elsevier Inc. All rights reserved.
10.1016/j.cell.2012.10.035

Referred to by: A Mediator Lost in the War on Cancer

Authors

  • Highlights
  • MED12 loss causes resistance to many cancer drugs through enhanced TGF-β signaling
  • MED12 inhibits TGF-β receptor signaling through physical interaction in the cytoplasm
  • MED12-regulated genes are predictive for responses to cancer drugs in patients
  • MED12-deficient tumors may benefit from therapy that includes a TGF-β inhibitor

Summary

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 MED12KD cells, suggesting a strategy to treat drug-resistant tumors that have lost MED12.

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