title: Selective Killing of SMARCA2- and SMARCA4-deficient Small Cell Carcinoma of the Ovary, Hypercalcemic Type Cells by Inhibition of EZH2:In VitroandIn VivoPreclinical Models.
abstract: The SWI/SNF complex is a major regulator of gene expression and is increasingly thought to play an important role in human cancer, as evidenced by the high frequency of subunit mutations across virtually all cancer types. We previously reported that in preclinical models, malignant rhabdoid tumors, which are deficient in the SWI/SNF core component INI1 (SMARCB1), are selectively killed by inhibitors of the H3K27 histone methyltransferase EZH2. Given the demonstrated antagonistic activities of the SWI/SNF complex and the EZH2-containing PRC2 complex, we investigated whether additional cancers with SWI/SNF mutations are sensitive to selective EZH2 inhibition. It has been recently reported that ovarian cancers with dual loss of the redundant SWI/SNF components SMARCA4 and SMARCA2 are characteristic of a rare rhabdoid-like subtype known as small-cell carcinoma of the ovary hypercalcemic type (SCCOHT). Here, we provide evidence that a subset of commonly used ovarian carcinoma cell lines were misdiagnosed and instead were derived from a SCCOHT tumor. We also demonstrate that tazemetostat, a potent and selective EZH2 inhibitor currently in phase II clinical trials, induces potent antiproliferative and antitumor effects in SCCOHT cell lines and xenografts deficient in both SMARCA2 and SMARCA4. These results exemplify an additional class of rhabdoid-like tumors that are dependent on EZH2 activity for survival.Mol Cancer Ther; 16(5); 850-60. ©2017 AACR.
authors.affiliation: Epizyme Inc., Cambridge, Massachusetts.
authors.forename: Elayne
authors.initials: E
authors.lastname: Chan-Penebre
authors.affiliation: Epizyme Inc., Cambridge, Massachusetts.
authors.forename: Kelli
authors.initials: K
authors.lastname: Armstrong
authors.affiliation: Epizyme Inc., Cambridge, Massachusetts.
authors.forename: Allison
authors.initials: A
authors.lastname: Drew
authors.affiliation: Epizyme Inc., Cambridge, Massachusetts.
authors.forename: Alexandra R
authors.initials: AR
authors.lastname: Grassian
authors.affiliation: Epizyme Inc., Cambridge, Massachusetts.
authors.forename: Igor
authors.initials: I
authors.lastname: Feldman
authors.affiliation: Epizyme Inc., Cambridge, Massachusetts.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Knutson
authors.affiliation: Epizyme Inc., Cambridge, Massachusetts.
authors.forename: Kristy
authors.initials: K
authors.lastname: Kuplast-Barr
authors.affiliation: Epizyme Inc., Cambridge, Massachusetts.
authors.forename: Maria
authors.initials: M
authors.lastname: Roche
authors.affiliation: Epizyme Inc., Cambridge, Massachusetts.
authors.forename: John
authors.initials: J
authors.lastname: Campbell
authors.affiliation: Epizyme Inc., Cambridge, Massachusetts.
authors.forename: Peter
authors.initials: P
authors.lastname: Ho
authors.affiliation: Epizyme Inc., Cambridge, Massachusetts.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Copeland
authors.affiliation: Epizyme Inc., Cambridge, Massachusetts.
authors.forename: Richard
authors.initials: R
authors.lastname: Chesworth
authors.affiliation: Epizyme Inc., Cambridge, Massachusetts.
authors.forename: Jesse J
authors.initials: JJ
authors.lastname: Smith
authors.affiliation: Epizyme Inc., Cambridge, Massachusetts.
authors.forename: Heike
authors.initials: H
authors.lastname: Keilhack
authors.affiliation: Epizyme Inc., Cambridge, Massachusetts. sribich@epizyme.com.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Ribich
mesh_terms: D000818:Animals; D018288:Carcinoma, Small Cell / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics*; D003937:Diagnosis, Differential; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000037:antagonists & inhibitors / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006801:Humans; D006934:Hypercalcemia / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D051379:Mice; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018335:Rhabdoid Tumor / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D009687:Nuclear Proteins; C084011:SMARCA2 protein, human; C445179:SWI-SNF-B chromatin-remodeling complex; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase; C084108:SMARCA4 protein, human; D004265:DNA Helicases