Tazemetostat (Tazverik) is a targeted therapy medication used to treat specific cancers. It is approved for patients aged 16 and older with epithelioid sarcoma that is metastatic or locally advanced and cannot be surgically removed. The drug is also used for adults with follicular lymphoma whose cancer has returned or has not responded to other treatments.
The Role of EZH2 in Cancer
Epigenetics is the system for controlling which genes are active or inactive. This system adds small chemical tags to DNA that act like switches, turning genes on or off without changing the DNA code itself. One of the enzymes in this process is the Enhancer of zeste homolog 2 (EZH2). EZH2 is part of a protein complex called PRC2, and its primary job is to turn genes off.
EZH2 performs this function by adding a methyl group to proteins called histones, which act as spools for DNA. EZH2 methylates a spot on histone H3 known as lysine 27. When this location is tagged with three methyl groups, the DNA in that region becomes more compact. This makes the genes inaccessible and effectively silences them, a normal process for healthy cell development.
In some cancers, this mechanism becomes unregulated. The EZH2 gene can mutate, causing the enzyme to become overactive, or the cell may produce too much of it. This hyperactivity leads to the silencing of tumor suppressor genes, which are meant to protect the body from cancer. When these genes that control cell division are switched off by EZH2, cancer cells can grow and multiply without restraint.
This disruption is like having a light switch for a safety system permanently jammed in the “off” position. The genes that should be active to halt uncontrolled growth are silenced, allowing the cancer to progress. This over-silencing of tumor suppressor genes contributes to the development of certain malignancies, including specific lymphomas and sarcomas.
How Tazemetostat Inhibits EZH2
Tazemetostat is a selective inhibitor of the EZH2 enzyme. Its design allows it to target and disrupt the enzyme’s activity, addressing the uncontrolled gene silencing in certain cancers. As a small molecule inhibitor, its structure is small enough to enter cells and interact directly with its target.
The drug works through competitive inhibition. The EZH2 enzyme has an active site where it binds to a molecule called S-adenosyl methionine (SAM), the source of the methyl groups used for gene silencing. Tazemetostat’s molecular structure mimics SAM, allowing it to fit into this same active site.
By occupying the active site, tazemetostat physically blocks SAM from binding to the EZH2 enzyme. This obstruction prevents EZH2 from methylating histones. Because tazemetostat competes for the same spot as the enzyme’s natural partner molecule, it shuts down the enzyme’s activity.
This inhibition occurs for both the normal (wild-type) and mutated forms of EZH2. This makes it effective in cancers driven by either an overabundance of the normal enzyme or by a hyperactive mutated version. The drug’s ability to selectively block this single enzyme target minimizes its effects on other cellular processes, which is the basis of its action as a targeted therapy.
Downstream Cellular Effects of Inhibition
Once tazemetostat blocks the EZH2 enzyme, a cascade of events begins inside the cancer cell. With EZH2 inhibited, the placement of methyl tags onto the histones of tumor suppressor genes stops. This allows the cell’s machinery to remove existing tags, loosening the DNA around these genes. The previously silenced tumor suppressor genes become accessible and can be read by the cell again.
The re-expression of these genes restores the cell’s safeguards against uncontrolled growth. When these tumor suppressor genes are turned back on, they can initiate processes that are detrimental to the cancer cell. One outcome is cell cycle arrest, which stops cancer cells from dividing and creating new cells.
Another effect is the induction of cellular differentiation. Cancer cells are often stuck in an immature, rapidly dividing state. The reactivation of certain genes can push these cells to mature into more specialized, non-dividing cell types, halting their malignant behavior. For B-cell lymphomas, this can prompt cells to exit the germinal center, a site of rapid B-cell proliferation, as a normal step in their maturation.
Finally, the restored gene activity can trigger apoptosis, or programmed cell death. Healthy cells have mechanisms to self-destruct when damaged or no longer needed, a process often disabled in cancer cells. By reactivating the genes that control this process, tazemetostat can cause cancer cells to eliminate themselves, reducing tumor size.
Clinical Relevance in Specific Cancers
The mechanism of tazemetostat is relevant for cancers with a specific dependency on EZH2 activity. Genetic testing and biomarker analysis are used to identify patients most likely to respond to the therapy. This allows doctors to match the drug to cancers that are biologically vulnerable to EZH2 inhibition.
In epithelioid sarcoma, the cancer is characterized by the loss of a tumor suppressor protein called INI1 (or SMARCB1). The INI1 protein is part of a complex that counteracts the activity of EZH2. When INI1 is absent, the cells become reliant on EZH2 for their survival and growth. By blocking EZH2 with tazemetostat, a pathway supporting the cancer’s proliferation is shut down.
For follicular lymphoma, the relevance is tied to specific mutations within the EZH2 gene. Some patients have “gain-of-function” mutations, like the Y641 mutation, which cause the EZH2 enzyme to become hyperactive. In these cases, tazemetostat directly counters the genetic driver of the disease by inhibiting this overactive enzyme. The drug is effective in patients with these mutations and in those with the normal, wild-type version of the enzyme.