'Window of Vulnerability'

Drug could boost chemotherapy in some lung cancers

The new study suggests that genetic tumor screening for <i>BGR1</i> mutations would be beneficial. Image: ffikretow/iStock

The new study suggests that genetic tumor screening for <i>BGR1</i> mutations would be beneficial. Image: ffikretow/iStock

An existing drug may help some patients with non-small cell lung cancer (NSCLC) whose tumors have become resistant to chemotherapy, according to lab studies by Harvard Medical School researchers at Boston Children’s Hospital and the Dana-Farber Cancer Institute.

The study, conducted in human cancer cells and in mice, suggests a window of vulnerability in NSCLC, the leading cause of cancer-related deaths worldwide. The work was published online Jan. 28 in Nature.

NSCLC is a highly genetically complex cancer with many different subtypes, each bearing different mutations. Two common subtypes, tumors with BRG1 or EGFR mutations, can become resistant to standard chemotherapy. The researchers were able to increase the effectiveness of a common chemotherapy agent, etoposide, for these subtypes in lab tests by adding an epigenetic therapy that inhibits an enzyme called EZH2.

When the same epigenetic therapy was added to certain tumors that did not have BRG1 or EGFR mutations, the tumors became more resistant to chemotherapy.

Together, the findings advance the idea of individualized “precision medicine” in cancer, incorporating epigenetic therapy guided by tumor genetic testing.

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

If what the research team found in lab dishes and mice proves to be true in humans, “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 the study’s first author, Christine Fillmore, HMS research fellow in genetics in Boston Children’s Stem Cell Program.

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—part of the cell’s so-called 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, HMS professor of medicine at Dana-Farber and Boston Children’s 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, HMS associate professor of genetics at Boston Children’s.

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

The study was supported in part by the National Institutes of Health (R01 HL090136, U01 HL100402, RFA-HL-09-004, CA122794, CA140594, CA163896, CA166480, CA154303, CA120964, K08 CA163677 and the Intramural Research Program), the American Cancer Society (RSG-08-082-01-MGO), the V Foundation for Cancer Research, a Basil O’Conner March of Dimes Starter Scholar Research Award, the Harvard Stem Cell Institute and the Lung Cancer Research Foundation.

Adapted from a Boston Childrens news release.