Tyrosine Kinase Inhibitors
Tyrosine kinase inhibitors selectively block oncogenic kinase signaling, revolutionizing targeted cancer therapy with improved efficacy and tolerability.
Overview
Tyrosine kinase inhibitors (TKIs) competitively block ATP binding to kinase domains, preventing phosphorylation of downstream signaling proteins. Oncogenic kinases are constitutively active drivers of malignant proliferation; their inhibition selectively impairs tumor cell survival. The development of imatinib for CML established TKIs as a paradigm of precision oncology.
BCR-ABL Inhibitors (CML/ALL)
Imatinib (Gleevec) was the first approved TKI, targeting BCR-ABL in CML, KIT in GIST, and PDGFR. It achieves complete cytogenetic remission in >80% of CML patients. Resistance occurs via T315I gatekeeper mutation, which blocks imatinib binding.
Second-generation TKIs (dasatinib, nilotinib, bosutinib) overcome most imatinib resistance mutations except T315I. Ponatinib (third-generation) is active against T315I but has vascular toxicity risks.
EGFR Inhibitors (NSCLC)
EGFR mutations (exon 19 deletions, L858R) predict sensitivity to EGFR TKIs in NSCLC. First-generation (erlotinib, gefitinib), second-generation (afatinib, dacomitinib), and third-generation (osimertinib) agents have successive efficacy against acquired resistance mutations. The T790M gatekeeper mutation causes resistance to first- and second-generation agents; osimertinib specifically targets T790M-mutant EGFR and is now first-line for EGFR-mutant NSCLC.
ALK/ROS1 Inhibitors
ALK rearrangements occur in ~5% of NSCLC. Crizotinib (first-generation), ceritinib, alectinib (second-generation), and lorlatinib (third-generation) have sequential activity against emerging resistance mutations. Alectinib has superior CNS penetration, important for brain metastases.
VEGFR and Multi-Kinase Inhibitors
Sorafenib inhibits VEGFR, PDGFR, RAF kinases, and others; used in HCC and RCC. Sunitinib targets VEGFR and KIT; used in GIST (imatinib-resistant), RCC, and pNET. Cabozantinib inhibits VEGFR2, MET, and RET.
Key Takeaways
- TKIs block ATP binding to activated kinase domains, selectively impairing oncogenic signaling
- Resistance mutations at gatekeeper residues (T315I in ABL, T790M in EGFR) drive sequential TKI development
- Osimertinib targets both activating EGFR mutations and T790M resistance
- Multi-kinase inhibitors (sorafenib, sunitinib) target angiogenic and oncogenic pathways simultaneously