title: SWI/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2.
abstract: Human cancer genome sequencing has recently revealed that genes that encode subunits of SWI/SNF chromatin remodeling complexes are frequently mutated across a wide variety of cancers, and several subunits of the complex have been shown to have bona fide tumor suppressor activity. However, whether mutations in SWI/SNF subunits result in shared dependencies is unknown. Here we show that EZH2, a catalytic subunit of the polycomb repressive complex 2 (PRC2), is essential in all tested cancer cell lines and xenografts harboring mutations of the SWI/SNF subunits ARID1A, PBRM1, and SMARCA4, which are several of the most frequently mutated SWI/SNF subunits in human cancer, but that co-occurrence of a Ras pathway mutation is correlated with abrogation of this dependence. Notably, we demonstrate that SWI/SNF-mutant cancer cells are primarily dependent on a non-catalytic role of EZH2 in the stabilization of the PRC2 complex, and that they are only partially dependent on EZH2 histone methyltransferase activity. These results not only reveal a shared dependency of cancers with genetic alterations in SWI/SNF subunits, but also suggest that EZH2 enzymatic inhibitors now in clinical development may not fully suppress the oncogenic activity of EZH2.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kimberly H
authors.initials: KH
authors.lastname: Kim
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Woojin
authors.initials: W
authors.lastname: Kim
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Howard
authors.affiliation: Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Francisca
authors.initials: F
authors.lastname: Vazquez
authors.affiliation: Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Aviad
authors.initials: A
authors.lastname: Tsherniak
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.|Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Wu
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Weishan
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Haswell
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Loren D
authors.initials: LD
authors.lastname: Walensky
authors.affiliation: Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.|Howard Hughes Medical Institute, Boston, Massachusetts, USA.
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.|Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Howard Hughes Medical Institute, Boston, Massachusetts, USA.
authors.forename: Charles W M
authors.initials: CW
authors.lastname: Roberts
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D002384:Catalysis / Q000187:drug effects; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D000071221:Enhancer of Zeste Homolog 2 Protein; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008745:Methylation / Q000187:drug effects; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism*; D011728:Pyridones / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004791:Enzyme Inhibitors; C577920:GSK-2816126; D007211:Indoles; D011728:Pyridones; D034741:RNA, Small Interfering; C445179:SWI-SNF-B chromatin-remodeling complex; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2