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