EZH2 inhibitors are a class of medications that combat cancer by targeting the EZH2 enzyme. This enzyme regulates gene activity, a fundamental process for normal cell development. They block excessive EZH2 activity, hindering tumor formation. As a targeted therapy, they precisely interfere with molecular pathways involved in cancer growth.
Understanding EZH2
The Enhancer of Zeste Homolog 2 (EZH2) is an enzyme. Its primary function involves modifying histones, which are proteins that DNA wraps around to form chromatin. Specifically, EZH2 catalyzes the addition of three methyl groups to lysine 27 on histone H3 (H3K27me3), a modification that typically leads to the silencing of gene transcription. This process is part of epigenetics, where gene expression is altered without changes to the underlying DNA sequence itself.
In healthy cells, EZH2’s activity is controlled, influencing various cellular processes like cell cycle progression, DNA repair, and cell differentiation. However, in various cancers, EZH2 often becomes overactive or mutated, leading to an imbalance in gene regulation. This dysregulation can result in the inappropriate silencing of tumor suppressor genes, which normally prevent uncontrolled cell growth. Enhanced EZH2 activity can promote uncontrolled cell growth, contributing to tumor development, spread, and resistance to therapies.
Mechanism of EZH2 Inhibitors
EZH2 inhibitors directly block the enzymatic activity of the EZH2 protein. They prevent EZH2 from adding methyl groups to histone H3 at the lysine 27 position. This inhibition disrupts the formation of the H3K27me3 mark, which is associated with gene silencing.
This inhibition restores normal gene expression patterns within cancer cells. When tumor suppressor genes are no longer silenced by excessive EZH2 activity, they can produce proteins that suppress cell proliferation and encourage programmed cell death. This leads to a reduction in cancer cell growth and survival. The inhibitors reverse epigenetic changes that contribute to cancer progression, hindering tumor development.
Clinical Applications
EZH2 inhibitors are used for treating specific types of cancer where EZH2 dysregulation plays a driving role. Tazemetostat is the first EZH2 inhibitor approved by the United States Food and Drug Administration (FDA). It is approved for treating epithelioid sarcoma, a rare soft tissue cancer, and follicular lymphoma, a type of non-Hodgkin B-cell lymphoma. Tazemetostat is specifically used in patients with follicular lymphoma whose disease has relapsed or not responded to standard treatments.
In these cancers, EZH2 can be overexpressed or harbor activating mutations that contribute to disease progression. For instance, in follicular lymphoma, mutations in the EZH2 gene can make the enzyme more active, contributing to the cancer’s development. Another EZH2 inhibitor, valemetostat, received approval in Japan in 2022 for treating relapsed or refractory adult T-cell leukemia/lymphoma. Beyond these approved indications, EZH2 inhibitors are also under investigation for their potential in other malignancies, including diffuse large B-cell lymphoma, prostate cancer, and melanoma, where EZH2 overexpression is implicated.
Ongoing Research and Future Directions
Research into EZH2 inhibitors extends beyond currently approved drugs, with several compounds in various stages of clinical trials for a broader range of indications. Scientists are exploring the potential of these inhibitors in combination therapies, aiming to enhance their effectiveness and overcome drug resistance. For example, preclinical studies have shown that combining EZH2 inhibition with T-cell based immunotherapies can improve the shrinking of non-Hodgkin B-cell lymphomas. This combination appears to work by making lymphoma cells more visible to the immune system and by reprogramming anti-cancer T cells for more durable activity.
Further research is investigating how EZH2 inhibitors might overcome resistance to chemotherapy or radiation therapy by restoring the expression of tumor suppressor genes and sensitizing cancer cells to conventional treatments. Challenges in optimizing their use include understanding tumor heterogeneity and adaptive resistance mechanisms, which necessitate continued investigation into the precise role of EZH2 in different cancer types. The future involves exploring new combinations, identifying additional sensitive tumor types, and refining treatment strategies to improve patient outcomes.