EZH2 ENZYME INHIBITION IN NSCLC

NEW YORK (Reuters Health) - The combination of the topoisomerase II (TopoII) inhibitor etoposide and an EZH2 enzyme inhibitor may prove effective against lung tumors with certain specific epigenetic mutations, researchers report.

"The findings suggest that EZH2 inhibitors with TopoII (topoisomerase II) inhibitors could be a first-line precision medicine option for lung cancer patients with BRG1-mutant tumors," Dr. Carla F. Kim, from Boston Children's Hospital and Harvard Medical School, told Reuters Health by email. "There is currently no targeted therapy for BRG1-mutant lung cancer. We are very excited to move forward with more preclinical and clinical testing."

EZH2 is a methyltransferase inhibitor that is highly coexpressed with TopoII in primary non-small-cell lung cancer (NSCLC) cell lines.

Dr. Kim's team investigated the effects of EZH2 inhibition, in combination with etoposide, in 26 NSCLC cell lines.

Fourteen of these cell lines proved to be more sensitive to etoposide in combination with EZH2 inhibition than to etoposide alone, whereas 12 cell lines were less sensitive to etoposide in the presence of EZH2 inhibition.

All but two of the 14 sensitized cell lines harbored inactivating mutations in BRG1 or activating mutations in EGFR, whereas all but two of the 12 protected cell lines were wild type for those two genes.

BRG1-mutant tumors responded to EZH2 inhibition with increased S phase, anaphase bridging, apoptosis, and etoposide sensitivity, whereas EGFR and BRG1 wild-type tumors upregulated BRG1 in response to EZH2 inhibition and ultimately became more resistant to etoposide.

EGFR-mutant tumors appeared to be sensitive to dual EZH2 and TopoII inhibition because of the genetic antagonism between EGFR and BRG1, according to the January 28 Nature online report.

"We were most surprised that the combination of etoposide treatment and EZH2 inhibition was only beneficial in two particular subsets of lung cancer patients, those whose tumors bore mutations in EGFR or BRG1," Dr. Kim said. "It was equally surprising that the drug combination made the etoposide less effective in other lung cancer subsets."

"Epigenetic therapies can be combined with current standard of care chemotherapies to make them more effective," she explained. "However, like most drugs, epigenetic therapies work the best for specific genotypes of lung cancer. Therefore, testing these novel drugs, and their interactions with current chemotherapies, needs to be done in a genotype-controlled fashion."

"We actually uncovered an antagonistic effect of EZH2 inhibitor and TopoII inhibitors in BRG1/EGFR wild-type tumors, and that warns that if patients are not chosen correctly for treatment, a combination therapy could actually be less effective than the standard of care alone," Dr. Kim said.

"Many companies are already developing EZH2 inhibitors and some are already in clinical trials," Dr. Kim added. "If these studies fail to show benefit, it may be because tumor genotype was not a selection criterion for treatment. A patient's lung tumor genotype must be taken into consideration even with epigenetic therapy."

Dr. Leigh Ellis, from Roswell Park Cancer Institute, Buffalo, New York, has shown similar benefits of EZH2 inhibition in combination with etoposide in prostate cancer. He told Reuters Health by email, "Positive correlation of TopoIIa and EZH2 exist in multiple cancer types; therefore, our findings represent a potential to affect treatment strategies and understanding of aggressive cancer progression globally."

"Downstream genetic programs governed by TopoIIa and EZH2 may lead to potential biomarkers, allowing for earlier detection of aggressive/lethal prostate cancer phenotypes," Dr. Ellis said. "Further, by understanding these gene networks, more efficient targeted therapies may be tested, which will allow for successful treatment of prostate cancer patients with aggressive/lethal phenotypes."

Dr. Andrew Wang, from University of North Carolina, Chapel Hill, is a radiation oncologist whose research focuses on chemosensitization from a drug delivery perspective. He told Reuters Health by email, "This study highlights the importance of genomic and nongenomic (such as epigenetics, proteomics) approaches to cancer. It shows that one can take advantage of the mutations that tumors develop and develop agents to improve cancer treatment."

"There is a large body of data on cancer mutations," Dr. Wang noted. "However, aside from several success stories, most new mutations are not 'druggable' and the benefit of sequencing patients' tumors is not exactly clear. If this study's approach can be expanded, then genomic data becomes very important (targets become druggable)."

SOURCE: http://bit.ly/1KcMtex

Nature 2015.