Findings could help physicians target existing drugs to appropriate patients
An existing drug may help some patients with non-small-cell lung cancer (NSCLC) whose tumors have become resistant to chemotherapy, finds a study from Boston Children’s Hospital and the Dana-Farber Cancer Institute (DFCI). The findings, in human cancer cells and in mice, suggest a window of vulnerability in NSCLC, the leading cause of cancer-related deaths worldwide.1 The work was published online by the journal Nature.
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 an enzyme known as 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 percent 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,” says Christine Fillmore, PhD, of Boston Children’s Hospital’s Stem Cell Research Program, the study’s first author.
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, says oncologist Kwok-Kin Wong, MD, PhD, professor of medicine at DFCI 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,” says 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,” adds Wong. “That’s the great thing.”
Additional authors on the study were Chunxiao Xu, PhD, Haikuo Zhang, PhD, and Peter Hammerman, MD, PhD, of DFCI; Pooja Desai, Joanne Berry, and Samuel Rowbotham, PhD, of Boston Children’s Hospital; Yi-Jang Lin of Harvard Medical School; and Victor Marquez, PhD, of the National Cancer Institute.
The study was supported in part by the Ladies Auxiliary to the Veterans of Foreign Wars, PF-12-151-01-DMC from the American Cancer Society, and the Uniting Against Lung Cancer Young Investigator Award supported by Meryl Bralower (C.M.F.), Boston University Undergraduate Research Opportunities Program (P.T.D.), RO1 HL090136, U01 HL100402 RFA-HL-09-004, American Cancer Society Research Scholar Grant RSG-08-082-01-MGO, the V Foundation for Cancer Research, aBasil O’Conner March of Dimes Starter Award, the Harvard Stem Cell Institute, and the Lung Cancer Research Foundation (C.F.K.), the National Institutes of Health (NIH) grants CA122794, CA140594, CA163896, CA166480, CA154303 and CA120964 (K.K.W.), the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (V.E.M.), and the NIH grant K08 CA163677 (P.S.H.).
1. Jemal, A. et al. Global cancer statistics. CA: A Cancer Journal for Clinicians 61, 69-90, doi:10.3322/caac.20107 (2011).