tyrosine kinase inhibitors

MECHANISM - Tyrosine kinases phosphorylate tyrosine residues on substrate proteins and drive pathways such as RAS/MAPK, PI3K/AKT, and JAK/STAT. These pathways control proliferation, survival, and angiogenesis. - TKIs are mostly ATP-competitive. They bind the kinase domain and block autophosphorylation and downstream signaling. - Receptor TKs include EGFR, HER2, VEGFR, PDGFR, KIT, ALK, RET, MET, and FLT3. - Non-receptor TKs include ABL, SRC, JAK, and BTK.

KEY DRUGS BY TARGET (high-yield) - BCR-ABL (CML, Ph+ ALL): - Imatinib is first-generation. - Dasatinib, nilotinib, bosutinib, and ponatinib are later generations. - Ponatinib is active against T315I. - Asciminib is an allosteric STAMP inhibitor that is also active against T315I. - c-KIT/PDGFR (GIST): imatinib, sunitinib, and regorafenib. - EGFR (NSCLC with exon 19 deletion or L858R): - Erlotinib, gefitinib, afatinib, and osimertinib. - Osimertinib is third-generation and covers T790M, the main resistance mutation. - ALK (NSCLC with EML4-ALK): crizotinib, alectinib, brigatinib, and lorlatinib. - HER2 (breast cancer): lapatinib, neratinib, and tucatinib. - BTK (CLL, mantle cell lymphoma, Waldenström): ibrutinib, acalabrutinib, and zanubrutinib. - JAK (polycythemia vera, myelofibrosis): ruxolitinib. Tofacitinib, baricitinib, and upadacitinib are used in RA and other inflammatory diseases. - VEGFR/multikinase (RCC, HCC, thyroid cancer): sorafenib, sunitinib, pazopanib, axitinib, cabozantinib, and lenvatinib. - BRAF V600E (melanoma) is a serine/threonine kinase target, not a tyrosine kinase. Vemurafenib and dabrafenib are kinase inhibitors but not TKIs in the strict sense. - FLT3 (AML): midostaurin and gilteritinib. - RET: selpercatinib and pralsetinib.

CLINICAL SIGNIFICANCE - Imatinib transformed CML from a fatal disease into a chronic, manageable one. It is the prototype of targeted therapy. - Monitor response in CML with BCR-ABL transcript levels by PCR. - Resistance usually comes from kinase domain mutations (BCR-ABL T315I "gatekeeper"; EGFR T790M), amplification of the target, or bypass pathway activation (e.g., MET amplification).

ADVERSE EFFECTS (commonly tested) - Imatinib: fluid retention and edema, myelosuppression, nausea, and hepatotoxicity. It is a CYP3A4 substrate. - Dasatinib: pleural effusion and pulmonary hypertension. - Nilotinib: QT prolongation and hyperglycemia. - Ponatinib: arterial thrombosis and vascular occlusion. - EGFR inhibitors: acneiform rash (a marker of efficacy) and diarrhea. Interstitial lung disease is rare but serious. - VEGFR inhibitors (sunitinib, sorafenib): hypertension, hand-foot syndrome, impaired wound healing, hemorrhage, and hypothyroidism (sunitinib). - Lapatinib: hepatotoxicity and cardiotoxicity, which is less than with trastuzumab. - Ibrutinib: atrial fibrillation and bleeding. - JAK inhibitors: infections, including herpes zoster reactivation, plus thrombosis, malignancy, and MACE (boxed warning).

PHARMACOLOGY PEARLS - TKIs are given orally. - Many are metabolized by CYP3A4. Strong inducers such as rifampin and carbamazepine lower levels. Strong inhibitors such as ketoconazole and grapefruit juice raise levels. - Many are teratogenic. - TKIs differ from monoclonal antibodies, which end in "-mab" and act on extracellular domains. - Examples include cetuximab (EGFR), trastuzumab (HER2), and bevacizumab (VEGF ligand). - Antibodies are given IV. TKIs act intracellularly and are given orally.

BOARD TAKEAWAYS - CML with t(9;22) → imatinib. - GIST with c-KIT mutation → imatinib. - EGFR-mutant NSCLC → erlotinib, gefitinib, or osimertinib. - EML4-ALK NSCLC → alectinib or crizotinib. - Polycythemia vera with JAK2 V617F → ruxolitinib. - CLL or mantle cell lymphoma → BTK inhibitors.