Taking the EZ way: Targeting enhancer of zeste homolog 2 in B-cell lymphomas.

Enhancer of zeste homolog 2 (EZH2) is an epigenetic regulator that controls the normal biology of germinal B cells. Overexpression or mutation of EZH2 is associated with malignant transformation in a number of B-cell malignancies; thus, EZH2 inhibitors are an attractive therapeutic option for these targets. Several EZH2 inhibitors have entered clinical trials, but there remains an important question as to how EZH2 inhibitor mechanism of action differs in patients with mutant and wild-type EZH2. This review discusses the EZH2-driven mechanisms that lead to the development of B-cell lymphomas and act as therapeutic targets. Another key area of investigation is whether EZH2 inhibitors will work synergistically with existing immunomodulatory drugs and chemotherapy regimens. In summary, EZH2 inhibitors show potential as treatment for a range of B-cell lymphomas, and numerous clinical evaluations are currently underway.

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Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.

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Declaration of Competing Interest FM: Honoraria from Janssen. Consultant or advisory role with AbbVie, Bristol Myers Squibb, Celgene, Epizyme, Genmab, Gilead Sciences, Kymera, and Roche. Expert testimony for Roche. GS: Honoraria from AbbVie, Celgene, Gilead Sciences, Janssen, MorphoSys, Novartis, and Roche/Genentech. Consulting or advisory role with Alimera Sciences, BeiGene, Bristol Myers Squibb, Celgene, Debiopharm Group, Epizyme, Genmab, Gilead Sciences, Incyte, Janssen, Miltenyi Biotec, MorphoSys, Novartis, Roche/Genentech, and VelosBio. Research funded in part through the NIH/NCI Cancer Center support grant P30 CA008748. CLB: Research funding from Autolus, Bayer, Epizyme, Inc., Janssen, Novartis, Roche, and Xynomic. Consulting or advisory role with ADC Therapeutics, GLG, Juno/Celgene, Karyopharm, Kite, Life Sci, Seattle Genetics, and TG Therapeutics. Honoraria from DAVA Oncology, Medscape, and touchIME. Stock or ownership in Bristol Myers Squibb, Moderna, Novavax, Pfizer, Regeneron, and Viatris. HT: Honoraria from Bristol-Myers Squibb and Servier. Consulting or advisory role with Janssen, Karyopharm Therapeutics, and Roche. Travel, accommodations, and expenses from Roche. AC: Honoraria from Celgene and Takeda. Consulting or advisory role with AbbVie and Roche. Travel, accommodations, and expenses from Takeda, Janssen, and Gilead. TP: Honoraria from Bayer, Genentech, Gilead Sciences, Incyte, Pharmacyclics, and Seattle Genetics. Consulting or advisory role with Bayer, Celgene, Curis, Genentech, Gilead Sciences, Incyte, Kite/Gilead, Pharmacyclics, and Seattle Genetics. Speakers' bureau for Genmab. Research funding from AbbVie, Bayer, and Pharmacyclics/Janssen. JB: Consulting or advisory role with AbbVie, Adaptive Biotechnologies, AstraZeneca, Bayer, BeiGene, Epizyme, Genentech/Roche, Kura Oncology, Kymera, MorphoSys, Novartis, Seattle Genetics, and Verastem. Speakers' bureau for BeiGene and Seattle Genetics. AM: Consulting or advisory role: AstraZeneca, Bristol Myers-Squibb, Constellation, Daiichi Sankyo, Epizyme, Exo Therapeutics, Janssen, and KDAC. Research funding from AstraZeneca, Daiichi Sankyo, Epizyme, Janssen, and Sanofi.