EZH2 Inhibitors: How They Work and Their Use in Cancer

EZH2 inhibitors are a class of targeted therapy drugs for specific types of cancer. They function by targeting an enzyme involved in epigenetics, the system that controls which genes are turned on or off. By interfering with this enzyme when it is overactive in cancer, these drugs aim to restore normal cellular function and stop tumor growth. This approach offers a specialized strategy in cancer therapy.

The Role of EZH2 in Cellular Processes and Disease

Enhancer of Zeste Homolog 2 (EZH2) is an enzyme that plays a part in the epigenetic regulation of genes and is a component of the Polycomb Repressive Complex 2 (PRC2). Its primary function is to add a methyl group to a protein called histone H3. This process, histone methylation, at a location designated H3K27, leads to DNA compaction and the silencing of specific genes.

This gene silencing is a normal process for cellular differentiation and development. However, when EZH2 is dysregulated, it can contribute to cancer by becoming overexpressed or mutated, which causes it to be overly active.

This hyperactivity leads to the improper silencing of tumor suppressor genes, which normally control cell growth and repair DNA. When EZH2 silences these protective genes, it allows cancer cells to grow and divide uncontrollably. This direct link to cancer progression makes EZH2 a specific target for therapeutic intervention.

How EZH2 Inhibitors Work

EZH2 inhibitors are small molecule drugs designed to block the EZH2 protein’s activity. They function as competitive inhibitors, binding to the part of the enzyme where its natural target, S-adenosylmethionine (SAM), would normally attach. By occupying this site, the inhibitors prevent EZH2 from transferring methyl groups to histones.

The direct consequence is a reduction in the methylation of histone H3 at lysine 27 (H3K27). This modification, known as H3K27 trimethylation (H3K27me3), is a strong signal for gene silencing. When the inhibitor is present, H3K27me3 levels decrease, leading to a more open chromatin structure.

This change allows the cell’s machinery to access and reactivate previously silenced genes, including tumor suppressor genes. Restoring their expression can re-establish natural defenses against cancer, leading to decreased cell proliferation, increased programmed cell death (apoptosis), and reduced tumor growth.

Medical Applications of EZH2 Inhibitors

The targeted action of EZH2 inhibitors has led to their approval for treating cancers with EZH2 dysregulation. One approved drug, Tazemetostat, is used for adults and pediatric patients aged 16 and older with epithelioid sarcoma. This provides a treatment for a rare and aggressive soft tissue cancer that previously lacked effective options.

Tazemetostat is also approved for certain adult patients with follicular lymphoma, a type of non-Hodgkin lymphoma. Its use is indicated for patients with relapsed or refractory lymphoma who have a specific EZH2 mutation. It can also be used for those with relapsed or refractory follicular lymphoma who have no other satisfactory treatment options, regardless of their EZH2 mutation status.

These inhibitors can be used as a monotherapy, or sole treatment, and research is also exploring their effectiveness in combination with other cancer therapies. Patient selection is often guided by genetic testing to identify EZH2 mutations or other molecular markers that predict a positive response. This precision medicine approach helps tailor treatment to the individual’s cancer.

Ongoing Research and Development

Beyond their approved uses, EZH2 inhibitors are being researched to expand their application in oncology. Clinical trials are evaluating their safety and effectiveness in a wider range of cancers. This includes solid tumors and hematological malignancies that depend on the EZH2 pathway for growth.

A major area of investigation is using EZH2 inhibitors in combination therapies. Researchers are pairing these drugs with chemotherapy, other targeted therapies, and immunotherapy. The goals are to enhance the anti-tumor effect, overcome drug resistance, or make tumors more recognizable to the immune system.

The potential of EZH2 inhibitors for non-cancerous conditions is also being explored. Since EZH2 is involved in processes like inflammation, its inhibition could be beneficial in certain inflammatory or autoimmune diseases. This area of research is less developed than oncology applications but represents a potential future direction for these drugs.

Potential Side Effects and Patient Considerations

Treatment with EZH2 inhibitors is associated with potential side effects that can vary in severity. Common adverse effects include fatigue, nausea, and musculoskeletal pain. These are monitored by the healthcare team during treatment.

More serious side effects can also occur. One is myelosuppression, a condition where the bone marrow’s production of blood cells is reduced. This can lead to anemia, an increased risk of infections, and bleeding complications. Patients require regular blood tests to monitor their blood counts.

There is also a risk of developing secondary malignancies, such as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Although this risk is low, patients must discuss it with their doctors. Before starting treatment, patients should have a thorough discussion with their healthcare provider about the potential benefits and risks to make an informed decision.