Tyrosine kinase inhibitors (cancer treatment)
Tyrosine kinase inhibitors (TKIs) are a class of targeted antitumor drugs that specifically inhibit tyrosine kinase enzymes, which play a crucial role in regulating cell survival and proliferation. By blocking these enzymes, TKIs can effectively slow tumor growth and induce cancer cell death. They are particularly used to treat various cancers, including chronic myeloid leukemia, gastrointestinal stromal tumors, non-small-cell lung cancer, pancreatic cancer, renal cell carcinoma, HER2-positive breast cancer, and colorectal cancer.
TKIs can be categorized into two primary types: small molecule inhibitors, which are administered in tablet form and work by preventing ATP from binding to kinases, and biologic antibody inhibitors, given through slow intravenous infusion, that block ligand-binding sites on tyrosine kinase receptors. This selective targeting of overactive tyrosine kinases in tumor cells offers a significant advantage, as it minimizes damage to normal cells.
Despite their efficacy, TKIs can lead to side effects such as nausea, fatigue, and flu-like symptoms, which can often be managed with medication. Recent advancements have led to the FDA approval of new TKIs, enhancing treatment options and addressing challenges like resistance and different cancer types. As research progresses, additional TKIs are being developed to improve cancer treatment outcomes and manage side effects more effectively.
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Tyrosine kinase inhibitors (cancer treatment)
ATC CODE: 101XE
DEFINITION: Tyrosine kinase inhibitors are a class of antitumor drugs specifically targeting tyrosine kinase enzymes. These drugs are particularly effective in slowing tumor growth and killing tumor cells because these enzymes are important in determining cellular fate, including survival and proliferation.
Cancers treated:Chronic myeloid leukemia, gastrointestinal stromal tumors, non-small-cell lung cancer, pancreatic cancer, renal cell carcinoma, HER2-positive breast cancer, colorectal cancer
Subclasses of this group: Small molecule inhibitors, biologic antibody inhibitors
Delivery routes: Small molecule tyrosine kinase inhibitors are orally active and administered in tablet form. Biologic antibody tyrosine kinase inhibitors are administered by slow intravenous (IV) infusion, usually over the course of a few hours.
How these drugs work: Through basic scientific research, several proteins critical for cellular growth, survival, and proliferation have been identified. One of the largest classes of these proteins is known as tyrosine kinases. Kinases are enzymes and proteins that can perform a specific activity or function. Kinases transfer a phosphate group onto a substrate protein, a process called phosphorylation. In particular, tyrosine kinases add a phosphate group onto specific tyrosine amino acid residues in the substrate protein. Phosphorylation can perform many different functions, including activating the substrate protein through an “on-off” mechanism, inducing protein-protein interaction, and changing protein localization. The functional changes induced in the substrate protein are used in many different signaling pathways, including those important to relay growth and proliferation signals in cells.
Cells can react to many external stimuli, including circulating growth factors and hormones, through the binding of these ligands to cell surface receptors. Many of these receptors are tyrosine kinases themselves or signal directly to downstream tyrosine kinases after being activated. Therefore, the activity of tyrosine kinases is a critical part of the signaling required to transmit information from the outside of the cell to the cellular interior, affecting the fate of the cell. Tumor cells often hijack the normal essential function of tyrosine kinases, mutating these proteins to remain in a constitutive “on” state. Because the kinase activity is then unable to be halted, the signaling pathways are continuously activated, and uncontrolled cell growth and proliferation ensue.
Because of their importance in determining cellular fate, especially whether a cell will live or die, tyrosine kinases are a desirable target for anticancer chemotherapy. Two major categories of tyrosine kinase inhibitors are small molecule inhibitors and targeted biological therapy. The major mechanism of action of small molecule inhibitors is to inhibit the binding of adenosine triphosphate (ATP) to the kinase. Because tyrosine kinases use ATP as a source of phosphate groups to perform phosphorylation, the enzyme cannot phosphorylate substrate proteins, thereby reducing the activation of the downstream signaling pathways. The second major class of tyrosine kinase inhibitors is targeted therapy, using antibodies generated against the tyrosine kinase receptors on the cellular surface. These antibodies mainly work by blocking the ligand-binding sites on these receptors, inhibiting the binding and, thus, the activation of these receptors. One of the main benefits of using tyrosine kinase inhibitors as anticancer chemotherapy is that they can selectively target tumor cells compared to normal cells because tumor cells often depend on overactivated and overexpressed tyrosine kinases. The US Food and Drug Administration has approved new tyrosine kinase inhibitors in the 2020s, including repotrectinib, tepmetko, tagrisso, and rybrevant. These novel medications are used in conjunction with existing chemotherapy regimens to increase their cancer-fighting abilities. Tyrosine kinase inhibitors continue to be developed to overcome treatment resistance and address new cancers and conditions.
Side effects: The most common side effects of the oral small molecule inhibitors are nausea and vomiting, fatigue, muscle pain, fluid retention (swelling), and rash. In most cases, these symptoms can be effectively managed with medication, so that treatment can continue. The side effects caused by biologic antibody therapies are mainly induced by the actual administration of the drug. Many patients (more than 70 percent) experience flulike symptoms, including fever, chills, muscle aches, and nausea. These side effects are generally lessened with the administration of drugs such as acetaminophen.
Bibliography
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