Tyrosine Kinase Inhibitors (TKIs)

Tyrosine kinase inhibitors (TKIs) are targeted anticancer agents that block signaling pathways crucial for cancer cell growth and survival. Drugs like imatinib revolutionized treatment of CML and GIST by specifically inhibiting abnormal kinases such as BCR-ABL and c-KIT. Others like erlotinib or crizotinib target EGFR or ALK in lung cancer. While TKIs are generally better tolerated than chemotherapy, they have distinct side effects (e.g., rash, diarrhea, hepatotoxicity) and require careful monitoring for resistance and drug interactions. They exemplify the shift toward precision oncology based on molecular targets.

Mechanism of Action

• TKIs block tyrosine kinases, enzymes involved in signal transduction for cell growth and survival.
• They inhibit phosphorylation of proteins involved in pathways like RAS/MAPK and PI3K/AKT.
• Some TKIs are selective (target specific kinases), others are multi-targeted.

Common TKIs & Indications

Common Side Effects

1. Gastrointestinal: Nausea, diarrhea, anorexia
2. Dermatologic: Rash, dry skin, hand-foot syndrome (esp. sunitinib, sorafenib)
3. Hematologic: Cytopenias (esp. with imatinib, dasatinib)
4. Hepatotoxicity: Monitor liver enzymes
5. Cardiac: QT prolongation (nilotinib), cardiomyopathy
6. Fluid retention: Periorbital or peripheral edema (esp. imatinib)

Clinical Considerations

1. Drug Interactions: Metabolized via CYP3A4—watch for inhibitors/inducers.
2. Resistance: Can occur due to mutations (e.g., T315I in BCR-ABL).
3. Monitoring: CBCs, LFTs, ECG (QT interval), and molecular response (e.g., BCR-ABL PCR in CML).
4. Pregnancy: Many are teratogenic—avoid in pregnancy.