MED12 in cancer drug resistance

Targeted cancer drugs do not typically lead to long-term survival benefits owing to emergent drug resistance caused by secondary-site mutations in the targeted gene or mutations in genes downstream. René Bernards and colleagues report that suppression of MED12 confers drug resistance to multiple targeted cancer drugs in multiple cancer cell lines (Cell 151, 937–950, 2012). The authors conducted an in vitro RNA interference (RNAi) screen targeting 8,000 genes. They found that MED12 was the only gene whose suppression led to resistance to the ALK inhibitor crizotinib. They then performed an inverse screen with a short hairpin RNA (shRNA) library that covers all 518 human kinases to identify genes whose suppression would restore drug sensitivity. They found that suppression of TGFBR2 resensitized MED12^KD cells to crizotinib. Further experiments showed that treatment of multiple cancer cell lines with recombinant TGF-β conferred resistance to multiple targeted cancer drugs, as well as the widely used chemotherapy drug cisplatin. Finally, the authors tested the combination of a TGF-βR2 inhibitor with crizotinib in MED12^KD cells and observed a synergistic inhibitory effect. The authors suggest that the combination of TGF-βR2 inhibitors with targeted tyrosine kinase inhibitors might be an effective therapy for tumors with elevated TGF-β signaling.