Oncogenic deregulation of EZH2 as an opportunity for targeted therapy in lung cancer

Haikuo Zhang, Jun Qi, Jaime M. Reyes, Lewyn Li, Prakash K. Rao, Fugen Li, Charles Y. Lin, Jennifer A. Perry, Matthew A. Lawlor, Alexander Federation, Thomas De Raedt, Yvonne Y. Li, Yan Liu, Melissa A. Duarte, Yanxi Zhang, Grit S. Herter-Sprie, Eiki Kikuchi, Julian Carretero, Charles M. Perou, Jacob B. ReibelJoshiawa Paulk, Roderick T. Bronson, Hideo Watanabe, Christine Fillmore Brainson, Carla F. Kim, Peter S. Hammerman, Myles Brown, Karen Cichowski, Henry Long, James E. Bradner, Kwok Kin Wong

Research output: Contribution to journalArticlepeer-review

90 Scopus citations


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.

Original languageEnglish
Pages (from-to)1007-1021
Number of pages15
JournalCancer Discovery
Issue number9
StatePublished - Sep 2016

Bibliographical note

Funding Information:
G.S. Herter-Sprie was supported by the Deutsche Forschungsgemeinschaft (HE 6897/1-1). K.-K. Wong and C.M. Perou are supported by NIH/NCI 1R01CA195740-01. K.-K. Wong is also supported by NIH/NCI P01CA120964, 5R01CA163896-04, 5R01CA140594-07, 5R01CA122794-10, and 5R01CA166480-04 grants and the Gross-Loh Family Fund for Lung Cancer Research and Susan Spooner Family Lung Cancer Research Fund at Dana-Farber Cancer Institute. J.E. Bradner is supported by the Burroughs-Wellcome Fund, the William Lawrence and Blanche Hughes Foundation, and a Leukemia and Lymphoma Society SCOR grant.

Publisher Copyright:
© 2016 American Association for Cancer.

ASJC Scopus subject areas

  • Oncology


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