New research shows that inhibiting the histone modifier EZH2 may make non–small cell lung cancers harboring BRG1 or EGFR mutations more sensitive to etoposide, a common chemotherapy.

Beyond targeted treatments for non–small cell lung cancer (NSCLC), researchers are increasingly exploring the potential of therapies that influence DNA methylation and histone modification—two epigenetic processes frequently disrupted in cancer—against this disease.

One such epigenetic target is EZH2, a protein that silences various genes by adding methyl groups to histone H3, causing chromatin compaction. “High EZH2 expression correlates with a poor prognosis for NSCLC, which is why we decided to investigate the therapeutic possibilities of drugs that inhibit this enzyme,” says Carla Kim, PhD, an associate professor at Boston Children's Hospital in Boston, MA. She recently showed that EZH2 suppression may boost the sensitivity of two NSCLC subsets to etoposide, a standard chemotherapy that works in only a minority of patients (Nature 28 Jan 2015 [Epub ahead of print]).

When Kim and her team blocked EZH2 in NSCLC cells, they observed two distinct phenotypes: Some cells became more sensitive to etoposide, while others became more resistant to the drug's effects. The researchers found that the majority of sensitized cells harbored inactivating mutations in BRG1 or activating mutations in EGFR. On the other hand, cells resistant to etoposide in the wake of EZH2 inhibition were nearly all wild-type for both genes. In an EGFR-mutant mouse model of NSCLC, combining etoposide with EZH2 suppression significantly impeded tumor growth; however, this dual therapy was ineffective in mice with wild-type EGFR and BRG1.

Unlike EZH2, BRG1 remodels chromatin into a more open structure and helps topoisomerase II (TopoII)—the target of etoposide—ensure that DNA daughter strands separate completely during replication. “Without BRG1, TopoII can't do its job,” says Christine Fillmore, PhD, a postdoctoral fellow in the Kim laboratory and the study's first author.

The researchers noted that in BRG1-mutant NSCLC cells—rendered still more vulnerable to etoposide by EZH2 inhibition—the number of anaphase bridges, or entangled DNA daughter strands, increased, as did the rate of programmed cell death. EGFR-mutant NSCLC cells, also acutely sensitive to combined EZH2 suppression and etoposide, behaved similarly despite having wild-type BRG1. “For reasons we don't yet understand, EGFR-mutant cells aren't able to fully utilize BRG1, even though it's present,” Fillmore says.

“The clinical implications of our research are exciting,” Kim says, “because there are no specific drugs for BRG1-mutant NSCLC, and the EGFR-mutant subset inevitably becomes resistant to targeted therapy.”

“This study opens the door to a closer investigation of dual EZH2 and TopoII inhibition in certain disease settings,” agrees Katerina Politi, PhD, an assistant professor at Yale Cancer Center in New Haven, CT, who wasn't involved in the research. “It's a great example of how understanding the molecular consequences of specific mutations can inform the use of standard chemotherapy.”

Kim and Fillmore hope their findings will also guide patient selection for EZH2 inhibitors in development—there are several in clinical trials, although none is yet approved. “We still have to consider the tumor genotype, even with epigenetic therapy,” Kim says.

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