MED12 Is a General Determinant of Drug Response Free

Targeted therapies can elicit dramatic responses, but resistance often rapidly develops. Known mechanisms include secondary mutations of the drug target, activating downstream mutations, and activation of parallel pathways, but resistance often cannot be explained by such events. Huang and colleagues uncovered a distinct, broadly acting drug resistance mechanism through a large-scale RNA interference (RNAi) screen for genes required for ALK inhibitor sensitivity in a non–small cell lung cancer (NSCLC) cell line that identified MED12, encoding a subunit of the MEDIATOR transcriptional adaptor complex. MED12 loss also conferred resistance to EGFR, BRAF, and MEK inhibitors and cytotoxic agents in various cancer cell types. A second kinome library RNAi screen showed that knockdown of TGF-β receptor 2 (TGF-βR2) restored ALK inhibitor sensitivity in MED12-deficient NSCLC cells, and TGF-βR2 overexpression or TGF-β treatment was sufficient to confer resistance to targeted and cytotoxic therapies in the cell types in which MED12 knockdown also induced resistance. MED12 knockdown led to TGF-β target gene upregulation, but not through transcriptional activation of TGFBR2, an unexpected finding given the role of MED12 in the MEDIATOR complex. Surprisingly, a proportion of cellular MED12 was bound to TGF-βR2 in the cytoplasm independently of other MEDIATOR subunits and suppressed TGF-βR2 maturation and cell surface expression. Consistent with a role for MED12 in TGF-β regulation, the MED12-knockdown gene signature was suggestive of a partial epithelial–mesenchymal transition (EMT) and a TGF-βR inhibitor synergized with targeted agents to suppress growth of drug-resistant MED12-deficient cells. Together with the observation that the MED12-knockdown signature was predictive of poor outcome in several clinical contexts, these findings suggest that MED12 expression may be a broadly useful biomarker of drug response and provide a rationale for testing whether TGF-βR inhibitors reverse drug resistance associated with MED12 loss and EMT induction.

Huang S, Hölzel M, Knijnenburg T, Schlicker A, Roepman P, McDermott U, et al. MED12 controls the response to multiple cancer drugs through regulation of TGF-β receptor signaling. Cell 2012;151:937–50.

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