tyrosine kinase inhibitor
Summary
Tyrosine kinase inhibitors (TKIs) are targeted anticancer drugs that block phosphorylation activity of tyrosine kinases, enzymes involved in signal transduction pathways controlling cell growth, proliferation, and survival. They are used in cancers driven by specific kinase mutations or overexpression, such as CML (imatinib) and certain lung cancers (erlotinib, gefitinib). Many end in the suffix '-nib'.
Detail
Tyrosine kinases are enzymes that transfer phosphate groups from ATP to tyrosine residues on target proteins, activating downstream signaling cascades (e.g., RAS-MAPK, PI3K-AKT) that drive cell division and survival. In many cancers, mutations or translocations create constitutively active tyrosine kinases that drive oncogenesis. TKIs competitively bind the ATP-binding site of these kinases (small molecule inhibitors) or, in the case of monoclonal antibodies, block the extracellular receptor domain, halting aberrant signaling.
Key examples and boards associations: - Imatinib: inhibits BCR-ABL fusion protein in chronic myeloid leukemia (Philadelphia chromosome, t(9;22)); also inhibits c-KIT (GIST) and PDGFR. Major toxicity: fluid retention, edema, hepatotoxicity. - Dasatinib/Nilotinib: second-generation BCR-ABL inhibitors, used in imatinib-resistant CML. - Erlotinib/Gefitinib: EGFR inhibitors used in non-small cell lung cancer with EGFR mutations. - Sunitinib/Sorafenib: multi-targeted TKIs (VEGFR, PDGFR, c-KIT) used in renal cell carcinoma, GIST; toxicity includes hypertension and hand-foot syndrome. - Vemurafenib: technically a BRAF inhibitor (serine/threonine kinase) though grouped conceptually with targeted kinase inhibitors, used in BRAF V600E-mutant melanoma. - Ibrutinib: inhibits Bruton tyrosine kinase (BTK), used in CLL/mantle cell lymphoma.
Mechanistically important for boards: understanding that these are targeted therapies exploiting oncogene addiction, contrasted with traditional cytotoxic chemotherapy which affects all rapidly dividing cells. Resistance can develop via secondary kinase domain mutations (e.g., T315I mutation in BCR-ABL conferring imatinib resistance, requiring ponatinib).
Clinical pearls: TKIs are generally better tolerated than cytotoxic chemo but have unique toxicities (cardiotoxicity with certain agents, skin rash with EGFR inhibitors, QT prolongation). Understanding the specific kinase target and associated malignancy is high-yield for Step 1, while clinical use and toxicity monitoring is relevant for Step 2.
Sources
- First Aid for the USMLE Step 1
- Katzung's Basic and Clinical Pharmacology
- Robbins and Cotran Pathologic Basis of Disease
- UpToDate: Overview of tyrosine kinase inhibitors in oncology
Reviewed by AnkiBoss editorial — medical student review. Information here is for study reference only and is not medical advice. Spotted an error? Let us know.