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Development of secondary mutations in wild-type and mutant EZH2 alleles cooperates to confer resistance to EZH2 inhibitors | |
2016 | |
发表期刊 | ONCOGENE |
ISSN | 0950-9232 |
EISSN | 1476-5594 |
卷号 | 35期号:5页码:558-566 |
发表状态 | 已发表 |
DOI | 10.1038/onc.2015.114 |
摘要 | The histone methyltransferase Enhancer of Zeste Homolog 2 (EZH2) is frequently dysregulated in cancers, and gain-of-function (GOF) EZH2 mutations have been identified in non-Hodgkin lymphomas. Small-molecule inhibitors against EZH2 demonstrated anti-tumor activity in EZH2-mutated lymphomas and entered clinical trials. Here, we developed models of acquired resistance to EZH2 inhibitor EI1 with EZH2-mutated lymphoma cells. Resistance was generated by secondary mutations in both wild-type (WT) and GOF Y641N EZH2 alleles. These EZH2 mutants retained the substrate specificity of their predecessor complexes but became refractory to biochemical inhibition by EZH2 inhibitors. Resistant cells were able to maintain a high level of H3K27Me3 in the presence of inhibitors. Interestingly, mutation of EZH2 WT alone generated an intermediate resistance phenotype, which is consistent with a previously proposed model of cooperation between EZH2 WT and Y641N mutants to promote tumorigenesis. In addition, the findings presented here have implications for the clinical translation of EZH2 inhibitors and underscore the need to develop novel EZH2 inhibitors to target potential resistance emerging in clinical settings. |
URL | 查看原文 |
收录类别 | SCI |
WOS研究方向 | Biochemistry & Molecular Biology ; Oncology ; Cell Biology ; Genetics & Heredity |
WOS类目 | Biochemistry & Molecular Biology ; Oncology ; Cell Biology ; Genetics & Heredity |
WOS记录号 | WOS:000369548800003 |
WOS关键词 | EMBRYONIC STEM-CELLS ; SELECTIVE-INHIBITION ; LYSINE 27 ; LYMPHOMA ; METHYLTRANSFERASE ; METHYLATION ; POLYCOMB ; CANCER ; EPIGENETICS ; REGULATORS |
原始文献类型 | Article |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/120270 |
专题 | 个人在本单位外知识产出 |
通讯作者 | Hassan, A. Q.; Chan, H. M. |
作者单位 | 1.Novartis Inst BioMed Res, 250 Mass Ave, Cambridge, MA 02139 USA 2.China Novartis Inst BioMed Res, Shanghai, Peoples R China |
推荐引用方式 GB/T 7714 | Gibaja, V.,Shen, F.,Harari, J.,et al. Development of secondary mutations in wild-type and mutant EZH2 alleles cooperates to confer resistance to EZH2 inhibitors[J]. ONCOGENE,2016,35(5):558-566. |
APA | Gibaja, V..,Shen, F..,Harari, J..,Korn, J..,Ruddy, D..,...&Chan, H. M..(2016).Development of secondary mutations in wild-type and mutant EZH2 alleles cooperates to confer resistance to EZH2 inhibitors.ONCOGENE,35(5),558-566. |
MLA | Gibaja, V.,et al."Development of secondary mutations in wild-type and mutant EZH2 alleles cooperates to confer resistance to EZH2 inhibitors".ONCOGENE 35.5(2016):558-566. |
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