Tyrosine Kinase receptors

🧬 Tyrosine Kinase Receptors (RTKs) are transmembrane growth-factor receptors that regulate cell proliferation, differentiation, metabolism, migration, angiogenesis, and survival. They are tightly controlled in health 🌱 but frequently mutated or overexpressed in cancer 🦀. RTKs are therefore major targets of modern targeted anti-cancer therapy 💊.

🏗️ Structure of Tyrosine Kinase Receptors

• Extracellular Domain 🧲
  • Ligand-binding region (e.g. EGF, VEGF, PDGF, insulin).
  • Determines specificity of signalling.
• Transmembrane Domain 🧱
  • Single α-helix anchoring receptor in lipid membrane.
• Intracellular Tyrosine Kinase Domain ⚡
  • ATP-binding catalytic site.
  • Autophosphorylates tyrosine residues after activation.
  • Creates docking sites for adaptor proteins (Grb2, PI3K, STAT).

⚙️ Activation Mechanism (Step-by-Step)

• 🎯 Ligand Binding
• 🤝 Dimerization (homo- or heterodimer)
• 💥 Trans-autophosphorylation
• 📡 Downstream signalling cascades:
  • MAPK/ERK → proliferation
  • PI3K/Akt/mTOR → survival & metabolism
  • JAK/STAT → transcription activation

🔑 Major RTK Families

• EGFR (ErbB family) 🧲 – growth & proliferation
• HER2 (ErbB2) 🎗️ – breast cancer amplification
• VEGFR 🌱 – angiogenesis
• PDGFR 🫀 – mesenchymal growth
• FGFR 🧬 – development & skeletal growth
• c-KIT (CD117) 🧪 – stem cell & GIST biology
• MET 🚀 – invasion & metastasis
• Insulin receptor 🍬 – glucose metabolism

🏥 Clinical Significance

🦀 1️⃣ Cancer

• RTK mutation, amplification, or overexpression → constitutive activation.
• Examples:
  • EGFR mutations → non-small cell lung cancer (NSCLC)
  • HER2 amplification → breast cancer
  • c-KIT mutation → GIST
  • FLT3 mutation → AML

👶 2️⃣ Developmental Disorders

• FGFR mutations → achondroplasia.
• RET mutations → MEN2 syndrome.

❤️ 3️⃣ Cardiovascular & Metabolic

• VEGFR important in vascular growth.
• Insulin receptor dysfunction → diabetes.

💊 Drugs Targeting RTKs (High-Yield Clinical Section)

📌 Two Main Classes

• Monoclonal Antibodies (mAbs) 💉
  • Target extracellular domain.
  • Prevent ligand binding or receptor dimerization.
  • Examples:
    • Trastuzumab (HER2)
    • Cetuximab (EGFR)
    • Bevacizumab (VEGF ligand)
• Small Molecule Tyrosine Kinase Inhibitors (TKIs) 💊
  • Inhibit intracellular ATP-binding site.
  • Oral drugs.
  • Often end in “-tinib”.

🎯 Key RTK-Targeted Drugs & Uses

• Imatinib 💊
  • Targets BCR-ABL, c-KIT, PDGFR.
  • Uses: CML, GIST.
  • Side effects: fluid retention, myelosuppression.
• Erlotinib / Gefitinib 💊
  • EGFR inhibitors.
  • Use: EGFR-mutant NSCLC.
  • Side effects: acneiform rash (predicts response), diarrhoea.
• Osimertinib 💊
  • 3rd-gen EGFR inhibitor.
  • Active against T790M resistance mutation.
• Trastuzumab 💉
  • HER2 monoclonal antibody.
  • Use: HER2-positive breast cancer.
  • Key toxicity: cardiomyopathy (monitor EF).
• Sunitinib / Sorafenib 💊
  • Multi-target TKIs (VEGFR, PDGFR, c-KIT).
  • Use: renal cell carcinoma, HCC.
  • Side effects: hypertension, hand-foot syndrome.
• Lenvatinib 💊
  • VEGFR inhibitor.
  • Use: thyroid cancer, HCC.
• Rituximab 🧬
  • Targets CD20 (not RTK but commonly grouped in targeted biologics).
  • Use: NHL, autoimmune disease.

⚠️ Class Side Effects of TKIs

• 🩸 Hypertension (VEGF blockade reduces nitric oxide).
• 🌡️ Hand-foot syndrome.
• 💩 Diarrhoea.
• 🫀 QT prolongation (some agents).
• 🧬 Myelosuppression.
• 🧴 Acneiform rash (EGFR inhibitors).

🔄 Drug Resistance Mechanisms

• Secondary mutation (e.g., EGFR T790M).
• Alternative pathway activation (MET amplification).
• Histologic transformation (e.g., adenocarcinoma → small cell).

🧠 Exam Pearls

• “Tinib” = tyrosine kinase inhibitor 💊
• HER2 breast cancer → Trastuzumab.
• EGFR lung cancer → Osimertinib first-line.
• GIST → Imatinib (c-KIT).
• VEGF blockade → hypertension + proteinuria.
• Trastuzumab → cardiotoxicity (monitor echo).

📖 Summary: RTKs are master regulators of cell growth and survival. When mutated or amplified → cancer. Modern oncology targets them with monoclonal antibodies 💉 and small-molecule TKIs 💊. Understanding RTK biology explains both tumour behaviour and targeted drug toxicities. 🎯