6533b82dfe1ef96bd129140f
RESEARCH PRODUCT
Oncogenic Deregulation of EZH2 as an Opportunity for Targeted Therapy in Lung Cancer.
Jacob B. ReibelMelissa DuarteLewyn LiGrit S. Herter-sprieMyles BrownChristine Fillmore BrainsonHaikuo ZhangHenry W. LongCharles M. PerouJulian CarreteroPrakash RaoPeter S. HammermanKaren CichowskiJaime M. ReyesMatthew A. LawlorJennifer A. PerryFugen LiYan LiuJoshiawa PaulkThomas De RaedtKwok-kin WongJun QiJames E. BradnerRoderick T. BronsonCarla F. KimHideo WatanabeEiki KikuchiAlexander J. FederationYvonne Y. LiCharles Y. LinYanxi Zhangsubject
0301 basic medicineModels MolecularLung Neoplasmsmedicine.medical_treatmentMolecular ConformationGene ExpressionAntineoplastic Agentsmacromolecular substancesBiologymedicine.disease_causeArticleMalignant transformationTargeted therapy03 medical and health sciencesMiceStructure-Activity RelationshipCell Line TumormedicineAnimalsHumansEnhancer of Zeste Homolog 2 ProteinMolecular Targeted TherapyLung cancerPromoter Regions GeneticGene Expression ProfilingEZH2Cancermedicine.diseaseMagnetic Resonance ImagingXenograft Model Antitumor AssaysChromatinrespiratory tract diseasesGene Expression Regulation NeoplasticDisease Models Animal030104 developmental biologyCell Transformation NeoplasticEnhancer Elements GeneticOncologyDrug DesignCancer researchAdenocarcinomaKRASEpigenetic therapydescription
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. 949. This article is highlighted in the In This Issue feature, p. 932
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2016-08-31 | Cancer discovery |