XPO1 inhibitors are a class of targeted therapy drugs used in cancer treatment. These medicines interfere with a specific process inside cancer cells, disrupting their ability to grow and survive. By focusing on a single molecular target, this approach is designed to affect malignant cells more than healthy ones, offering a distinct method for managing certain cancers.
The Role of XPO1 in Cells
Within every healthy cell, a protein called Exportin 1 (XPO1) acts as a cellular shuttle. It is responsible for moving over 200 different regulatory proteins from the cell’s nucleus to the surrounding cytoplasm. This transport process ensures proteins are in the right place to control functions like cell growth, division, and programmed cell death, known as apoptosis.
In many cancers, this transport system is exploited by producing an excessive amount of XPO1. This leads to the accelerated removal of tumor suppressor proteins, like p53, from the nucleus. These proteins are meant to stay in the nucleus to repair DNA damage and stop uncontrolled cell division. When XPO1 pushes them out, they cannot perform their protective duties, allowing cancer cells to multiply without restraint.
This hijacking of the XPO1 shuttle contributes to the progression of various cancers, including blood cancers and solid tumors. The increased XPO1 activity disarms the cell’s natural defenses against tumor formation. By clearing the nucleus of these proteins, the cancer cell creates an environment that supports its own survival and proliferation.
Mechanism of Action
XPO1 inhibitors interfere with the overactive shuttle system in cancer cells by binding directly to the XPO1 protein. This binding creates a blockade, preventing XPO1 from attaching to its cargo of tumor suppressor proteins. As a result, the inhibitor makes it unable to transport these proteins out of the cell’s nucleus.
By blocking this exit route, XPO1 inhibitors cause tumor suppressor proteins like p53 to accumulate inside the nucleus. This forced nuclear retention allows them to resume their intended functions. They can then regulate cell division and monitor for DNA damage.
Once confined to the nucleus, these proteins can signal the cancer cell to halt its division cycle. They can also initiate apoptosis, or programmed cell death, a natural process for eliminating damaged cells. By blocking XPO1 transport, the inhibitors restore the cell’s ability to recognize it is malignant and trigger its self-destruction, helping to control the cancer’s growth.
Clinical Applications and Approved Treatments
The primary clinical application for XPO1 inhibitors is treating specific blood cancers, often for patients who have not responded to other therapies. The most prominent approved drug in this class is Selinexor (Xpovio). It is an oral medication that provides a targeted treatment option for persistent cancers.
Selinexor is approved by the U.S. Food and Drug Administration (FDA) for treating multiple myeloma, a cancer of plasma cells. It is often prescribed in combination with other drugs, such as dexamethasone and bortezomib. This treatment is for adult patients whose disease is relapsed or refractory, meaning it has returned or stopped responding after at least one prior therapy. For heavily pretreated patients, it can be used after four or more previous therapies have failed.
Another approved use for Selinexor is in treating diffuse large B-cell lymphoma (DLBCL), an aggressive type of non-Hodgkin lymphoma. It is indicated for adult patients with relapsed or refractory DLBCL who have undergone at least two previous lines of systemic therapy. Approval for these conditions was granted under the FDA’s accelerated approval program, allowing earlier access to promising drugs.
Common Side Effects and Management
Patients taking XPO1 inhibitors like Selinexor may experience side effects, as the treatment can affect healthy cells. The most reported issues include nausea, vomiting, diarrhea, loss of appetite, and fatigue. To manage this, patients are often given anti-nausea medications (antiemetics) before their dose, and appetite stimulants may be recommended to combat weight loss.
Selinexor also impacts blood cell counts, causing conditions like thrombocytopenia (low platelets), neutropenia (low white blood cells), and anemia (low red blood cells). Healthcare providers monitor blood counts closely, especially during the first few months of therapy. Dose adjustments or changing the treatment schedule are common strategies to lessen these effects.
Proactive management is a component of the treatment plan. Open communication between the patient and their medical team is necessary for promptly addressing side effects. This collaboration ensures the treatment can be continued safely and effectively.