Development of secondary mutations in wild-type and mutant EZH2 alleles cooperates to confer resistance to EZH2 inhibitors
Open accessAbstract
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.
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Preclinical data suggest that drug resistance to EZH2 inhibitors could be generated by secondary mutations in both wild-type and mutant EZH2 alleles.
“Although EZH2 inhibitors are promising antitumor agents, preclinical data suggest that drug resistance could be generated by secondary mutations in both wild-type and mutant EZH2 alleles [160].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [160]
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- Authors
- Gibaja, V, Shen, F., Harari, J., Korn, J., Ruddy, D., Saenz-Vash, V, Zhai, H., Rejtar, T., Paris, C. G., Yu, Z., Lira, M., King, D., Qi, W., Keen, N., Hassan, A. Q., & Chan, H. M.
- Affiliations
- Novartis (China) (CN)
- Corresponding author
- Hassan, A Q
- Chan, H M
- Venue
- Oncogene
- Published
- 2015-04-20
- Volume
- 35
- Issue
- 5
- Pages
- 558-566
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC4744243
- OpenAlex
- W2007171597
- Cited by
- 149
- References
- 32
- Citations by year
- 2026: 9 · 2025: 8 · 2024: 10 · 2023: 11 · 2022: 7 · 2021: 9 · 2020: 12 · 2019: 18 · 2018: 21 · 2017: 17 · 2016: 19 · 2015: 8
- FWCI
- 9.69
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Oncogene (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
- Keywords
- EZH2, EZH2 inhibitors, acquired drug resistance, secondary mutations, H3K27me3, histone methyltransferase, non-Hodgkin lymphoma, gain-of-function mutations, histone methylation, inhibitor resistance
- MeSH terms
- Enhancer of Zeste Homolog 2 Protein, Histone Methyltransferases, Alleles, Antineoplastic Agents, Histones, Humans, Lymphoma, Mutation, Histone-Lysine N-Methyltransferase, Drug Resistance, Neoplasm, Cell Line, Tumor, Cell Proliferation, Polycomb Repressive Complex 2
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