RRC ID |
62009
|
Author |
Chan-Penebre E, Armstrong K, Drew A, Grassian AR, Feldman I, Knutson SK, Kuplast-Barr K, Roche M, Campbell J, Ho P, Copeland RA, Chesworth R, Smith JJ, Keilhack H, Ribich SA.
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Title |
Selective Killing of SMARCA2- and SMARCA4-deficient Small Cell Carcinoma of the Ovary, Hypercalcemic Type Cells by Inhibition of EZH2: In Vitro and In Vivo Preclinical Models.
|
Journal |
Mol Cancer Ther
|
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.
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Volume |
16(5)
|
Pages |
850-860
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Published |
2017-5-1
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DOI |
10.1158/1535-7163.MCT-16-0678
|
PII |
1535-7163.MCT-16-0678
|
PMID |
28292935
|
MeSH |
Animals
Carcinoma, Small Cell / diagnosis
Carcinoma, Small Cell / drug therapy*
Carcinoma, Small Cell / genetics
Carcinoma, Small Cell / pathology
Cell Line, Tumor
Chromosomal Proteins, Non-Histone / genetics
DNA Helicases / genetics*
Diagnosis, Differential
Enhancer of Zeste Homolog 2 Protein / antagonists & inhibitors
Enhancer of Zeste Homolog 2 Protein / genetics*
Female
Gene Expression Regulation, Neoplastic / drug effects
Histone-Lysine N-Methyltransferase / genetics
Humans
Hypercalcemia / diagnosis
Hypercalcemia / drug therapy
Hypercalcemia / genetics
Hypercalcemia / pathology
Mice
Mutation
Nuclear Proteins / genetics*
Ovarian Neoplasms / diagnosis
Ovarian Neoplasms / drug therapy*
Ovarian Neoplasms / genetics
Ovarian Neoplasms / pathology
Rhabdoid Tumor / diagnosis
Rhabdoid Tumor / drug therapy*
Rhabdoid Tumor / genetics
Rhabdoid Tumor / pathology
Transcription Factors / genetics*
Xenograft Model Antitumor Assays
|
IF |
5.615
|
Resource |
Human and Animal Cells |
OVK18(RCB1903)
JHOC-5(RCB1520)
JHOC-7(RCB1688)
JHOC-8(RCB1723)
JHOC-9(RCB2226)
JHOS-2(RCB1521)
JHOS-4(RCB1678) |