Bruton Tyrosine Kinase (BTK) inhibitors inhibit the enzyme BTK, which is a crucial part of the B-cell receptor signaling pathway. Certain B-cell leukemias and lymphomas use B-cell receptor signaling for growth and survival.
The rationale for using BTK inhibitors in cancer, therefore, is to block this signaling and trigger the death of cancer cells.
What are Bruton Tyrosine Kinase (BTK) Inhibitors Used For?
Bruton Tyrosine Kinase (BTK) inhibitors are effective against:
Not all BTK inhibitors are approved for all these conditions.
How do Bruton Tyrosine Kinase (BTK) Inhibitors Work?
To explain how BTK inhibitors work, we first must explain what a B cell is, and what the B-cell receptor signaling pathway does.
B-cells, also known as B-lymphocytes, are a type of lymphocyte, which is a type of white blood cell. The surface of each B-lymphocyte contains around 10,000 protein complexes called membrane-bound antibodies. Antibodies may also be called immunoglobulins.
All the membrane-bound antibodies for one particular B-cell are the same; however, between B-cells, the antibodies vary slightly in their variable portion, meaning that there is a lot of diversity among B-cell membrane-bound antibodies (several billion).
This diversity means that if a foreign invader (also called an antigen) enters the body, such as a disease-causing bacteria or virus, there would be a B-cell with the right membrane-bound antibodies available to attach to it. As soon as a B-cell binds to the antigen, it becomes activated with the help of certain T cells and starts cloning itself, making hundreds of thousands of copies, and these start to differentiate, taking on certain roles. For example, memory cells that recognize the same antigen later, and effector cells that start producing unique antibodies for that particular invader.
B-cells also contain B-cell receptors. These receptors play a crucial role in the biology of normal B-cells and assist with the binding, internalization, and processing of the antigen. Stimulation of B-cell receptors induces the activation of multiple enzymes, including Bruton tyrosine kinase (BTK) which is part of the B-cell receptor signaling pathway that communicates with other cells of the immune system and results in B-cell proliferation and activation.
Research in the 1970s reported that B-cells could facilitate the growth of certain experimental tumors in mice. Since then, investigations have shown that B-cells account for up to 25% of all cells in some cancers. Infiltrating B-cells also play an important role in breast cancer and ovarian cancers.
By inhibiting the BTK enzyme involved in B-cell receptor signaling, BTK inhibitors cause the detachment of malignant B-cells from cancer sites into blood, which results in cell death. BTK inhibition reduces the proliferation of malignant B-cells and decreases the survival of malignant cells. However, the effects of BTK inhibitors also extend to nonmalignant cells, which accounts for their side effects.
What are the Side Effects of Bruton Tyrosine Kinase (BTK) Inhibitors?
BTK inhibitors have been associated with some severe side effects. Ibrutinib was the first BTK inhibitor approved in 2013, but subsequent BTK inhibitors are associated with fewer side effects.
Ibrutinib is associated with a high risk of bleeding (approximately 50% of patients develop minor bleeding), atrial fibrillation (16% of patients), and high blood pressure (almost 40% of patients with CLL taking ibrutinib develop high blood pressure).
Resistance to ibrutinib is also a problem. This means the medication no longer works as it should, and this is usually due to an acquired mutation. People who were progressing on ibrutinib, but who discontinue it abruptly, experience a more aggressive clinical progression of their disease, and overlapping the discontinuation of ibrutinib with a subsequent line of therapy is recommended. Ibrutinib is associated with cure rates of up to 18%.
Acalabrutinib has a more favorable safety profile than ibrutinib with high blood pressure occurring in 7% of patients, neutropenia in 11%, and pneumonia in 10%. Severe bleeding is not common. Acalabrutinib may be preferred in patients unable to tolerate ibrutinib because of coexisting conditions or toxicities. However, single-agent acalabrutinib is associated with low cure rates (around 2%) and combination therapy may be more effective.
The most common side effects associated with zanubrutinib include neutropenia (14%), anemia (8%), neutropenia (7%), and pneumonia (4%). High blood pressure was reported in only 3% of patients and atrial fibrillation in only 1.9%, mostly in individuals with predisposing risk factors. Minor hemorrhage was observed in 2.5% of patients. Cure rates with single-agent zanubrutinib of 3% have been reported.
Pirtobrutinib is a highly selective, non-covalent, reversible inhibitor of the BTK enzyme, unlike other BTK inhibitors that permanently bind to BTK. This allows cancer cells that have acquired resistance to other BTK inhibitors to respond again. Pirtobrutinib also has a lower rate of side effects than other BTK inhibitors, with the most common ones including fatigue (20%), diarrhea (17%), and bruising (13%). Only 1% developed atrial fibrillation and only 5 patients in clinical trials stopped treatment because of side effects.
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