PMID- 25893294
OWN - NLM
STAT- MEDLINE
DCOM- 20160726
LR  - 20181202
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 35
IP  - 5
DP  - 2016 Feb 4
TI  - Development of secondary mutations in wild-type and mutant EZH2 alleles 
      cooperates to confer resistance to EZH2 inhibitors.
PG  - 558-66
LID - 10.1038/onc.2015.114 [doi]
AB  - 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.
FAU - Gibaja, V
AU  - Gibaja V
AD  - Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
FAU - Shen, F
AU  - Shen F
AD  - Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
FAU - Harari, J
AU  - Harari J
AD  - Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
FAU - Korn, J
AU  - Korn J
AD  - Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
FAU - Ruddy, D
AU  - Ruddy D
AD  - Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
FAU - Saenz-Vash, V
AU  - Saenz-Vash V
AD  - Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
FAU - Zhai, H
AU  - Zhai H
AD  - Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
FAU - Rejtar, T
AU  - Rejtar T
AD  - Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
FAU - Paris, C G
AU  - Paris CG
AD  - Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
FAU - Yu, Z
AU  - Yu Z
AD  - China Novartis Institutes for BioMedical Research, Shanghai, China.
FAU - Lira, M
AU  - Lira M
AD  - Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
FAU - King, D
AU  - King D
AD  - Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
FAU - Qi, W
AU  - Qi W
AD  - China Novartis Institutes for BioMedical Research, Shanghai, China.
FAU - Keen, N
AU  - Keen N
AD  - Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
FAU - Hassan, A Q
AU  - Hassan AQ
AD  - Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
FAU - Chan, H M
AU  - Chan HM
AD  - Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
LA  - eng
PT  - Journal Article
DEP - 20150420
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Histones)
RN  - EC 2.1.1.- (Histone Methyltransferases)
RN  - EC 2.1.1.43 (EZH2 protein, human)
RN  - EC 2.1.1.43 (Enhancer of Zeste Homolog 2 Protein)
RN  - EC 2.1.1.43 (Histone-Lysine N-Methyltransferase)
RN  - EC 2.1.1.43 (Polycomb Repressive Complex 2)
SB  - IM
MH  - *Alleles
MH  - Antineoplastic Agents/*pharmacology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/genetics
MH  - Drug Resistance, Neoplasm
MH  - Enhancer of Zeste Homolog 2 Protein
MH  - Histone Methyltransferases
MH  - Histone-Lysine N-Methyltransferase/genetics/metabolism
MH  - Histones/genetics/metabolism
MH  - Humans
MH  - Lymphoma/*drug therapy/*genetics/pathology
MH  - *Mutation
MH  - Polycomb Repressive Complex 2/*antagonists & inhibitors/*genetics
PMC - PMC4744243
EDAT- 2015/04/22 06:00
MHDA- 2016/07/28 06:00
PMCR- 2016/02/06
CRDT- 2015/04/21 06:00
PHST- 2014/09/25 00:00 [received]
PHST- 2015/02/27 00:00 [revised]
PHST- 2015/03/06 00:00 [accepted]
PHST- 2015/04/21 06:00 [entrez]
PHST- 2015/04/22 06:00 [pubmed]
PHST- 2016/07/28 06:00 [medline]
PHST- 2016/02/06 00:00 [pmc-release]
AID - onc2015114 [pii]
AID - 10.1038/onc.2015.114 [doi]
PST - ppublish
SO  - Oncogene. 2016 Feb 4;35(5):558-66. doi: 10.1038/onc.2015.114. Epub 2015 Apr 20.