FLT3 inhibitors represent a class of targeted therapies that specifically address certain types of cancer. These medications are designed to interfere with the activity of a particular protein, known as FMS-like tyrosine kinase 3 (FLT3), which can become overactive in some cancer cells. By focusing on this specific molecular target, these inhibitors aim to disrupt the processes that drive uncontrolled cell growth and survival. This approach offers a more precise treatment strategy compared to conventional chemotherapy, which often affects both healthy and cancerous cells.
The Role of FLT3 in Cancer
The FLT3 gene provides instructions for making the FLT3 protein, a type of receptor tyrosine kinase. In healthy individuals, this protein is primarily found on the surface of early blood-forming cells, known as hematopoietic progenitor cells, where it helps regulate their normal growth, division, and maturation into various blood cell types. Activation of the FLT3 receptor initiates a signaling cascade inside the cell, promoting the survival and differentiation of these immature cells into mature blood cells.
However, certain changes, or mutations, within the FLT3 gene can lead to the production of an abnormal or overactive FLT3 protein. These mutations can cause the protein to be constantly switched “on,” sending continuous growth signals to the cell. This uncontrolled signaling can result in the rapid and unregulated proliferation of abnormal blood cells. These genetic alterations effectively transform FLT3 into an oncogene, a gene that can promote cancer development. The presence of these specific FLT3 mutations makes the cancer cells dependent on the abnormal FLT3 signaling for their survival and growth.
How FLT3 Inhibitors Work
FLT3 inhibitors function by directly interfering with the activity of the mutated FLT3 protein. The FLT3 protein is a kinase, an enzyme that adds phosphate groups to other proteins, thereby acting as a molecular switch to activate various cellular processes. In cancer cells with FLT3 mutations, this kinase activity is abnormally high, leading to continuous activation of downstream signaling pathways that promote cell growth and survival.
FLT3 inhibitors are small molecule drugs designed to bind to the FLT3 receptor, effectively blocking its activation. These inhibitors prevent the FLT3 protein from sending its aberrant growth signals. This disruption cuts off the continuous “on” switch that drives the proliferation of cancerous blood cells. As a result, the abnormal signaling cascade is halted, which can lead to a reduction in cancer cell growth and, in some cases, induce programmed cell death in the malignant cells. This targeted approach aims to selectively impact cancer cells that rely on the mutated FLT3 protein, sparing healthy cells to a greater extent than traditional chemotherapy.
Approved FLT3 Inhibitors and Their Use
Several FLT3 inhibitor drugs have received approval for the treatment of acute myeloid leukemia (AML), particularly in patients whose leukemia cells carry specific FLT3 gene mutations. These mutations commonly include internal tandem duplications (FLT3-ITD) and tyrosine kinase domain mutations (FLT3-TKD).
- Midostaurin (Rydapt): Approved for newly diagnosed adults with FLT3-mutated AML, often with chemotherapy.
- Gilteritinib (Xospata): Used for adults with FLT3-mutated AML that has relapsed or not responded to previous treatments.
- Quizartinib (Vanflyta): Indicated for newly diagnosed FLT3-mutated AML patients in combination with chemotherapy, with potential for maintenance therapy.
- Sorafenib (Nexavar): A multi-kinase inhibitor with activity against FLT3, sometimes used, though not specifically FDA-approved for AML.
Important Considerations for Patients
Patients undergoing treatment with FLT3 inhibitors may experience a range of side effects that require careful management. Common side effects can include gastrointestinal issues such as nausea and diarrhea, as well as fatigue and skin rashes. Some patients might also experience a decrease in blood cell counts, a condition known as myelosuppression.
Another important consideration is the potential for QTc prolongation, an electrical change in the heart that can be detected via an electrocardiogram (ECG). Regular ECGs are often performed to monitor heart rhythm during treatment. Patients will also undergo frequent blood tests to check blood counts and liver and kidney function. Adherence to the prescribed treatment schedule is important for the effectiveness of the therapy. Open communication with the healthcare team about any symptoms or concerns allows for timely intervention and adjustments to the treatment plan.