Reference Detail

Ref Type

Journal Article

PMID

(27312177)

Authors

Zhang H, Qi J, Reyes JM, Li L, Rao PK, Li F, Lin CY, Perry JA, Lawlor MA, Federation A, De Raedt T, Li YY, Liu Y, Duarte MA, Zhang Y, Herter-Sprie GS, Kikuchi E, Carretero J, Perou CM, Reibel JB, Paulk J, Bronson RT, Watanabe H, Brainson CF, Kim CF, Hammerman PS, Brown M, Cichowski K, Long H, Bradner JE, Wong KK

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	6	9	2016 Sep	1006-21	Cancer Discov

URL

Abstract Text

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.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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
JQEZ5	JQEZ5	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
JQEZ5		JQEZ-5\|JQE5	EZH2 inhibitor 20	JQEZ5 inhibits EZH2, which may result in decreased growth of EZH2-overexpressing tumors (PMID: 27312177, PMID: 31711520).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References