Oncogenic Deregulation of EZH2 as an Opportunity for Targeted Therapy in Lung Cancer.
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.
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
Haikuo
H
Zhang
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
Jun
J
Qi
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Jaime M
JM
Reyes
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts.
Lewyn
L
Li
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts.
Prakash K
PK
Rao
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts.
Fugen
F
Li
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Charles Y
CY
Lin
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Jennifer A
JA
Perry
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Matthew A
MA
Lawlor
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Alexander
A
Federation
Department of Medicine, Harvard Medical School, Boston, Massachusetts. Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Thomas
T
De Raedt
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
Yvonne Y
YY
Li
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
Yan
Y
Liu
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts.
Melissa A
MA
Duarte
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
Yanxi
Y
Zhang
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
Grit S
GS
Herter-Sprie
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
Eiki
E
Kikuchi
Department of Physiology, University of Valencia, Burjassot, Valencia, Spain.
Julian
J
Carretero
Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Charles M
CM
Perou
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
Jacob B
JB
Reibel
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Joshiawa
J
Paulk
Department of Microbiology and Immunobiology, Division of Immunology, Harvard Medical School, Boston, Massachusetts.
Roderick T
RT
Bronson
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
Hideo
H
Watanabe
Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts. Harvard Stem Cell Institute, Cambridge, Massachusetts. Department of Genetics, Harvard Medical School, Boston, Massachusetts.
Christine Fillmore
CF
Brainson
Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts. Harvard Stem Cell Institute, Cambridge, Massachusetts. Department of Genetics, Harvard Medical School, Boston, Massachusetts.
Carla F
CF
Kim
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
Peter S
PS
Hammerman
Department of Medicine, Harvard Medical School, Boston, Massachusetts. Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts.
Myles
M
Brown
Department of Medicine, Harvard Medical School, Boston, Massachusetts. Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Karen
K
Cichowski
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts.
Henry
H
Long
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.
James E
JE
Bradner
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.
Kwok-Kin
KK
Wong
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015195:Drug Design; D004742:Enhancer Elements, Genetic; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D058990:Molecular Targeted Therapy; D011401:Promoter Regions, Genetic; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D002843:Chromatin; D000071221:Enhancer of Zeste Homolog 2 Protein