Epigenetic drug boosts efficacy of chemotherapy in some lung cancers

Epigenetic drug boosts efficacy of chemotherapy in some lung cancers
Epigenetic drug boosts efficacy of chemotherapy in some lung cancers

An existing drug may help some patients with non-small cell lung cancer (NSCLC) whose tumors have become resistant to chemotherapy, finds a study published in Nature (2015; doi:10.3322/caac.20107). The findings, in human cancer cells and in mice, suggest a window of vulnerability in NSCLC, which is the leading cause of cancer-related deaths worldwide.

NSCLC is a highly genetically complex cancer with many different subtypes, each bearing different mutations. In two common subtypes that do not respond to standard chemotherapy, tumors with BRG1 or EGFR mutations, the researchers increased the effectiveness of etoposide, a common chemotherapy agent, by adding an epigenetic therapy already in clinical testing.

Conversely, when the same epigenetic therapy (inhibition of the enzyme EZH2) was added to certain tumors without BRG1 and EGFR mutations, the tumors become more resistant to chemotherapy. Together, the findings advance the idea of individualized, precision medicine in cancer, incorporating epigenetic therapy guided by tumor genetic testing.

The study also suggests that genetic tumor testing should screen for mutations in BRG1, a natural tumor suppressor. This test is not done widely now, although testing does look for EGFR mutations and other known cancer-driver mutations. An estimated 10% of patients with NSCLC have BRG1 mutations, and this genetic subtype currently lacks a targeted therapy.

"Etoposide plus an EZH2 inhibitor could be a first-line therapy for BRG1-mutant tumors, and a treatment option for EGFR-mutant tumors that are resistant to tyrosine kinase inhibitors," said first author Christine Fillmore, PhD, of Boston Children's Hospital's Stem Cell Research Program, in Massachusetts.

EZH2 has been strongly linked with cancer progression and is part of a complex of molecules that determine which genes in a cell are turned on or off, which are part of the cell's epigenome. Epigenetic therapy has become a hot area in cancer research, and EZH2 inhibitors are in phase I/II trials for other cancers, including B cell lymphomas and malignant rhabdoid tumors.

However, the use of EZH2 inhibitors in lung cancer has needed more rationale in preclinical studies, said oncologist Kwok-Kin Wong, MD, PhD, professor of medicine at Dana-Farber Cancer Institute and Harvard Medical School and a collaborator on the study. The researchers hope their findings will inspire the pharmaceutical industry to test EZH2 inhibitors together with chemotherapy in patients whose tumors have BRG1 or EGFR mutations.

"This study provides better predictive information as to which cancer patients will respond to EZH2 inhibitors, and shows that even epigenetic therapy needs to be specified to a genotype," said senior author Carla Kim, PhD, an associate professor at Boston Children's Stem Cell Program and the Department of Genetics at Harvard Medical School.

"We don't have to invent new drugs. The drugs are already out there," added Wong. "That's the great thing."

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