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What are tyrosine kinase inhibitors?
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Elevated levels of tyrosine kinases are observed in certain types of cancer cells.
Tyrosine kinase inhibitors are a type of targeted therapy that stop the action of tyrosine kinases, which are enzymes that are a part of cell signaling, growth and division.
TKIs are used to treat various malignancies, such as chronic myelogenous leukemia and acute lymphoblastic leukemia. They include imatinib (Gleevec, Novartis), gefitinib (Iressa, AstraZeneca), erlotinib (Tarceva; Genentech, Astellas), sorafenib (Nexavar, Bayer), sunitinib (Sutent, Pfizer) and dasatinib (Sprycel, Bristol-Myers Squibb).
These therapies come in the form of capsules or pills and are taken once or twice daily. They target different tyrosine kinases and result in varying degrees of treatment-associated adverse effects. Some TKIs block one type of tyrosine kinase, whereas others block multiple enzymes and are known as multi-TKIs.
TKIs have been known to have serious drug-to-drug interactions if taken along with other medications and should not be taken with grapefruit or pomegranate. TKI therapy should not be taken during pregnancy, as it will cause harm to the fetus.
Types of TKIs
Imatinib is a first-generation TKI used to treat CML. It was the first therapy to specifically target the BCR-ABL tyrosine kinase protein. Although most patients treated with imatinib respond well to the therapy for years, patients are required to stay on the therapy indefinitely.
Some patients experience resistance to the TKI and if an increase in the dose does not work, these patients are required to switch to another TKI.
Another type of TKI that targets the BCR-ABL protein is dasatinib. This second-generation TKI is used to treat CML and is often prescribed when a patient cannot withstand the side effects of imatinib or when the therapy stops working.
One of the newer TKIs is ponatinib, which also targets the BCR-ABL protein. However, this TKI is accompanied by serious side effects and is, therefore, only used to treat CML that has not responded to any other TKI therapy or if the patient’s cancer cells have a T315I mutation. This mutation prevents other TKIs from being effective. Ponatinib is the first approved TKI effective against CML cells that have this mutation.
Adverse effects
There are common mild adverse effects associated with TKIs. These include diarrhea, nausea, muscle pain, skin rash and fatigue. More serious adverse effects include fluid buildup around the eyes, abdomen, lungs or feet; and a decrease in white blood cell and platelet counts.
Adverse effects specifically associated with ponatinib include an increased risk for blood clots, which may lead to heart attacks and strokes. In rare cases, blood clots in patients taking this drug have cut off circulation, leading to amputation. Blood clots are more common in patients with high blood pressure, high cholesterol or diabetes, as well as those who have already had a heart attack, stroke or poor circulation.
Looking ahead
Researchers are seeking new ways to block the growth factors that trigger the cancer cells to divide and grow, including lowering levels of the growth factor in the body, blocking the growth factor receptor on the cancer cell and blocking the signals inside the cell that start up when the growth factor triggers the receptor.
For more information:
www.uofmhealth.org/health-library/tv7950