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Cancer Discov. 2016 Sep;6(9):1006-21. doi: 10.1158/2159-8290.CD-16-0164. Epub 2016 Jun 16.

Oncogenic Deregulation of EZH2 as an Opportunity for Targeted Therapy in Lung Cancer.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
2
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
3
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts.
4
Department of Medicine, Harvard Medical School, Boston, Massachusetts. Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
5
Department of Physiology, University of Valencia, Burjassot, Valencia, Spain.
6
Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
7
Department of Microbiology and Immunobiology, Division of Immunology, Harvard Medical School, Boston, Massachusetts.
8
Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts. Harvard Stem Cell Institute, Cambridge, Massachusetts. Department of Genetics, Harvard Medical School, Boston, Massachusetts.
9
Department of Medicine, Harvard Medical School, Boston, Massachusetts. Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts.
10
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts. kwong1@partners.org james_bradner@dfci.harvard.edu.
11
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts. Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts. kwong1@partners.org james_bradner@dfci.harvard.edu.

Abstract

As a master regulator of chromatin function, the lysine methyltransferase EZH2 orchestrates transcriptional silencing of developmental gene networks. Overexpression of EZH2 is commonly observed in human epithelial cancers, such as non-small cell lung carcinoma (NSCLC), yet definitive demonstration of malignant transformation by deregulated EZH2 remains elusive. Here, we demonstrate the causal role of EZH2 overexpression in NSCLC with new genetically engineered mouse models of lung adenocarcinoma. Deregulated EZH2 silences normal developmental pathways, leading to epigenetic transformation independent of canonical growth factor pathway activation. As such, tumors feature a transcriptional program distinct from KRAS- and EGFR-mutant mouse lung cancers, but shared with human lung adenocarcinomas exhibiting high EZH2 expression. To target EZH2-dependent cancers, we developed a potent open-source EZH2 inhibitor, JQEZ5, that promoted the regression of EZH2-driven tumors in vivo, confirming oncogenic addiction to EZH2 in established tumors and providing the rationale for epigenetic therapy in a subset of lung cancer.

SIGNIFICANCE:

EZH2 overexpression induces murine lung cancers that are similar to human NSCLC with high EZH2 expression and low levels of phosphorylated AKT and ERK, implicating biomarkers for EZH2 inhibitor sensitivity. Our EZH2 inhibitor, JQEZ5, promotes regression of these tumors, revealing a potential role for anti-EZH2 therapy in lung cancer. Cancer Discov; 6(9); 1006-21. ©2016 AACR.See related commentary by Frankel et al., p. 949This article is highlighted in the In This Issue feature, p. 932.

PMID:
27312177
PMCID:
PMC5010480
DOI:
10.1158/2159-8290.CD-16-0164
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

P.K.R. is a consultant to Selecta Biosciences Inc, Watertown, MA. J.E.B. is a Scientific Founder of SHAPE Pharmaceuticals, Acetylon Pharmaceuticals, Tensha Therapeutics and C4 Therapeutics and is the inventor on IP licensed to these entities. J.E.B. currently an employee of Novartis Institutes of Biomedical Research.

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