Drug resistance biomarker could improve cancer treatment

A new study has revealed a biomarker, MED12, that can predict responses to cancer drugs and offers a strategy to treat drug-resistant tumors based on their genetic signature. This key gene determines resistance to a range of cancer drugs.

Cancer therapies often have short-lived benefits because genetic mutations emerge that cause drug resistance. Non-small cell lung cancer (NSCLC) is the most common type of cancer, and NSCLC patients with a specific type of tumor mutation can be treated with crizotinib, a targeted therapy. However, drug resistance frequently develops through secondary mutations that occur through unknown genetic mechanisms.

This study sought to gain insight into these mechanisms by developing a screen to identify genes whose suppression confers resistance to crizotinib in NSCLC cells. The investigators found that inhibiting MED12, a gene that is mutated in cancers, resulted in resistance to not only crizotinib, but also other targeted drugs and chemotherapy used to treat various types of cancer.

Further, MED12 suppression caused drug resistance by enhancing signaling through the transforming growth factor beta receptor (TGF-betaR), which is a protein involved in cell growth and cell death. By inhibiting TGF-betaR signaling in MED12 deficient cells, they were able to restore drug responsiveness. The results suggest that TGF-betaR inhibitors, which are currently being tested in clinical trials, may counter drug resistance in cancer patients with MED12 mutations.

“We need to understand the mechanisms of drug resistance to effectively prevent it from occurring in the first place,” said senior study author Professor René Bernards of the Netherlands Cancer Institute. “We have identified a mechanism of drug resistance that is caused by the activation of a specific signaling pathway in cancer cells. We have shown that blocking this escape route restores sensitivity to the original drug, suggesting a way to treat patients that have undergone this type of drug resistance.”

This study was published in Cell (2012; doi:10.1016/j.cell.2012.10.035).
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