Targeted therapies (kinase inhibitors)

Kinase Inhibitors - Flipping the Off Switch

• Mechanism: Competitively inhibit ATP binding to the catalytic site of tyrosine kinases (TKs), preventing phosphorylation and blocking downstream signaling pathways. This halts uncontrolled cell proliferation.
• Suffix: Most end in -tinib (e.g., Imatinib, Erlotinib).

⭐ Imatinib is a first-line treatment for Chronic Myelogenous Leukemia (CML) by targeting the BCR-ABL fusion protein, a constitutively active tyrosine kinase.

BCR-ABL Inhibitors - CML's Kryptonite

• Target: BCR-ABL tyrosine kinase, a constitutively active enzyme from the Philadelphia chromosome t(9;22) translocation, driving Chronic Myeloid Leukemia (CML).
• Mechanism: Competitively inhibit the ATP-binding site of the BCR-ABL kinase, ↓ downstream signaling, inducing apoptosis in cancer cells.
• Drugs ("-nibs"):
  • Imatinib (Gleevec): First-line therapy.
  • Dasatinib, Nilotinib: Second-generation; more potent, used in imatinib resistance.
  • Ponatinib: Active against the resistant T315I mutation.

⭐ Resistance can develop via point mutations in the kinase domain (e.g., T315I "gatekeeper" mutation), rendering most TKIs ineffective.

EGFR & ALK Inhibitors - Lung Cancer Erasers

Target non-small cell lung cancer (NSCLC) with specific driver mutations. Actionable mutations are key before therapy.

BRAF/MEK/VEGFR Inhibitors - Melanoma & More

• BRAF Inhibitors: Vemurafenib, Dabrafenib
  • MOA: Inhibit BRAF kinase with V600E mutation.
  • Use: Metastatic melanoma.
  • AEs: Rash, arthralgia, photosensitivity.
• MEK Inhibitors: Trametinib, Cobimetinib
  • MOA: Inhibit MEK, downstream of BRAF.
  • Use: Combine with BRAF inhibitors to delay resistance.
• VEGFR Inhibitors: Sorafenib, Sunitinib
  • MOA: Multi-kinase inhibitors blocking angiogenesis.
  • Use: Renal Cell & Hepatocellular Carcinoma.
  • AEs: Hypertension, hand-foot syndrome, hemorrhage.

⭐ Paradoxical MAPK pathway activation by BRAF inhibitors in wild-type cells can cause secondary cutaneous squamous cell carcinomas.

Toxicity & Resistance - The Price of Precision

• Universal Toxicities: Fatigue, diarrhea, rash, myelosuppression.
• Signature Toxicities:

⭐ Exam Favorite: The T315I "gatekeeper" mutation in the BCR-ABL gene confers resistance to most TKIs (e.g., imatinib) but not ponatinib.

High‑Yield Points - ⚡ Biggest Takeaways

• Kinase inhibitors are targeted therapies that selectively block oncogenic kinases, unlike traditional chemotherapy.
• Most small molecule inhibitors end in "-tinib" (tyrosine kinase inhibitor) or "-rafenib" (RAF kinase inhibitor).
• Key examples: Imatinib for CML (BCR-ABL) and Vemurafenib for melanoma (BRAF V600E).
• EGFR inhibitors (e.g., Erlotinib) for NSCLC classically cause an acneiform rash.
• Common toxicities include rash, diarrhea, and potential QT prolongation.
• Acquired resistance via secondary kinase mutations is a major clinical limitation.