Researchers have found a novel cellular mechanism that determines resistance to various targeted cancer therapies and several different cancers. The gene may be a key biomarker that could predict responses and provide better strategies to treat drug-resistant cancers. The results, led by researchers at the Netherlands Cancer Institute are published in Cell.
The team identified the MED12 gene in a large-scale RNA interference screen. MED12 is a part of a transcriptional complex called MEDIATOR that is found mutated in many cancers. The gene controls the response to several cancer drugs through a signaling pathway known to be important for cancer. The gene was found to be crucial for resistance to crizotinib (Xalkori), a targeted non–small-cell lung cancer (NSCLC) drug, MEK and BRAF inhibitors, and chemotherapy.
Cancer resistance remains a major problem for both chemotherapy treatment and targeted agents. While patients harboring a specific mutation often respond to a targeted agent, the responses are generally short-lived as the tumor develops genetic resistance to the therapy. Resistance is particularly difficult to address as there is high variability in terms of resistance mechanisms among different patients. Understanding whether a cancer patient will be susceptible to a specific therapy is a major goal for researchers.
René Bernards, PhD, professor and head of the Molecular carcinogenesis group at the Netherlands Cancer Institute in Amsterdam, and colleagues developed a screen to identify genes that when inactivated, result in resistance to crizotinib in a NSCLC cell line with the EML4-ALK translocation. This translocation is the target of crizotinib, making the cell line initially susceptible to this drug. When MED12 was inactivated in NSCLC and other cancer cell lines, it led to resistance of crizotinib. Further experiments also found that MED12 inactivation conferred resistance to chemotherapy and other drugs currently used to treat melanoma, liver, and colon cancers.
The crux of the drug resistance mechanism, it turns out, is MED12 inactivity results in higher activity of the transforming growth factor β (TGF-β) signaling pathway. Tumors that have the TGF-β pathway active are often associated with a poor prognosis. One way the TGF-β pathway could promote a more aggressive phenotype is by activation of genes that then activate the epithelial–mesenchymal transition (EMT).
“EMT is believed by many, if not all, to be an essential stage during metastasis. Cells undergoing EMT and cells during metastasis both have reduced proliferative capacity but elevated defense against apoptosis, apparently making them more resistant to certain anticancer therapies,” said Xing Guo, PhD, a postdoctoral fellow in the department of pharmacology at the University of California San Diego, and Xiao-Fan Wang, PhD, department of pharmacology at the Duke University Medical Center, coauthors of the commentary accompanying the study. EMT also confers migratory capabilities to cells, allowing them to travel.
The TGF-β pathway, said Guo, "has many target genes, regulates many cellular activities, and works on many cell types. Its effects on drug resistance and cancer metastasis are manifestations of the broad functions of this pathway.”
The results demonstrate a way to predict whether a cancer patient is resistant to treatment. The major finding of this study, said Bernards, is that “TGF-β induced EMT is a factor in resistance to a broad range of cancer drugs.”
The team showed that growth of cells without MED12 could only be blocked with a combination of a TGF-β inhibitor and a tyrosine kinase inhibitor, but neither one worked alone. The next step to address this mechanism of tumor resistance is combination treatment. “Combination therapy of such EMT tumors with a TGF-β inhibitor. This should restore drug response,” said Bernards. The research team will be testing this approach in the clinic soon.
Bernards believes that colon cancers may benefit most from TGF-β inhibitor therapy. Colon cancers with upregulated EMT have been found to have a poor prognosis and the current study shows these types of tumor cells are resistant to chemotherapy-based treatment. “That means that EMT colon cancer cells are double trouble: more likely to metastasize, less likely to respond to therapy,” said Bernards. Bernards would like to work with a pharmaceutical or biotechnology company to test this approach.
To better understand exactly how TGF-β signaling and the activity of EMT genes results specifically in chemotherapy resistance is also an important goal for Bernards in colleagues. TGF-β signaling has been linked to signaling of the RAS-RAF-MEK pathway that drugs such as vemurafenib (Zelboraf) target. Bernards and colleagues observed that cells with inactive MED12 had active RAS-RAF-MEK signaling which persisted even in the presence of crizotinib, gefitinib(Drug information on gefitinib) (Iressa), vemurafenib, selumetinib, and sorafenib(Drug information on sorafenib) (Nexavar)—drugs that are supposed to block the activity of this pathway. This explains why MED12 inactivity results in resistance to these drugs. How activity of these pathways result in chemotherapy resistance is not yet known, however.
“Important discoveries can come totally unexpected, like the finding of MED12,” said Guo, pointing out the power of unbiased high-throughput screens. “Researchers should be open-minded and willing to think outside the box.”
Guo and Wang see this study adding to the evidence that cancer needs individualized, combination strategies. Thus far, no single targeted drug has led to a cure. “When we think about cancer drugs, target specificity is good, but not enough,” said Guo. Genetic analysis as well as understanding the relationship of cancer cells to the stroma and developing markers of diagnosis and prognosis will be important to better understand and treat cancer.