TKI

TKI stands for tyrosine kinase inhibitor, a class of small molecule drugs that block the enzymatic activity of tyrosine kinases. Tyrosine kinases are enzymes that transfer phosphate groups to tyrosine residues on proteins, a key step in signaling pathways that regulate cell growth, survival, and angiogenesis. Many cancers harbor abnormalities that drive kinase signaling, making TKIs a targeted therapeutic approach.

Most TKIs are ATP-competitive, binding to the kinase ATP-binding pocket to prevent phosphorylation. Some are highly selective for a single kinase, while others inhibit multiple kinases involved in tumor growth and tumor blood vessel formation. They are typically administered orally and can vary in pharmacokinetics and tissue distribution. TKIs can be used as monotherapy or in combination with chemotherapy, immunotherapy, or other targeted agents, depending on the molecular characteristics of the tumor.

The clinical impact of TKIs began with imatinib, which revolutionized treatment for chronic myeloid leukemia and certain gastrointestinal stromal tumors. Since then, dozens of TKIs have been developed for a range of cancers, targeting kinases such as BCR-ABL, EGFR, ALK, ROS1, MET, VEGFR, RET, and KIT. Examples include imatinib, dasatinib, nilotinib, ponatinib; gefitinib, erlotinib, afatinib; crizotinib; sorafenib, sunitinib, pazopanib, and others. These drugs have improved survival and quality of life in selected patient populations, though responses can be limited by resistance and adverse effects.

Common challenges include acquired resistance due to mutations, amplification, or alternative pathway activation, as well as side effects like rash, diarrhea, hypertension, hepatotoxicity, cytopenias, and QT prolongation. Ongoing research focuses on next-generation TKIs, combination strategies, and biomarker-driven patient selection to extend benefits and overcome resistance.