Receptor tyrosine kinases (RTKs) are transmembrane proteins that convert extracellular growth factor signals into intracellular kinase activity, initiating proliferative and survival cascades. With ~58 RTKs encoded in the human genome (ErbB, VEGFR, MET, FGFR, RET, ALK, ROS1 families), RTK dysregulation through mutation, amplification, or autocrine ligand loops is among the most common oncogenic events in carcinoma. Critically, RTKs are the most tractable class of oncoproteins for therapeutic targeting — both by small-molecule TKIs that occupy the ATP-binding pocket and by monoclonal antibodies targeting the extracellular domain.
Ligand binding induces RTK dimerisation, which triggers trans-autophosphorylation of intracellular tyrosine residues. These phosphotyrosines serve as docking platforms for SH2-domain-containing adaptor proteins (GRB2, SHC, p85/PI3K), scaffolding the assembly of signalling complexes that activate RAS/MAPK and PI3K/AKT cascades. Signal termination is achieved by c-CBL-mediated RTK ubiquitination and lysosomal degradation, and by PTEN/phosphatase-mediated PIP3 dephosphorylation.
Ligand binding induces RTK dimerisation, which triggers trans-autophosphorylation of intracellular tyrosine residues. These phosphotyrosines serve as docking platforms for SH2-domain-containing adaptor proteins (GRB2, SHC, p85/PI3K), scaffolding the assembly of signalling complexes that activate RAS/MAPK and PI3K/AKT cascades. Signal termination is achieved by c-CBL-mediated RTK ubiquitination and lysosomal degradation, and by PTEN/phosphatase-mediated PIP3 dephosphorylation.
Receptor Tyrosine Kinase Activation
Dimerised RTK kinase domains adopt an asymmetric configuration: one kinase (activator) catalytically phosphorylates tyrosines in the other (receiver). The pattern of phosphotyrosines determines which signalling pathways are preferentially activated.
HER3 (kinase-dead RTK) is the most potent PI3K activator in the ErbB family due to 6 YXXM motifs that directly recruit p85-PI3K. HER2/HER3 heterodimers generate maximal PI3K/AKT signalling without requiring adaptor intermediates — explaining the exceptional pro-survival drive of HER2-amplified tumours.
c-CBL E3 ligase ubiquitinates activated EGFR at Tyr1045, promoting receptor internalisation via clathrin-coated vesicles or macropinocytosis. Endosomal receptors are either degraded (lysosomal) or recycled (Rab11-dependent). Autocrine ligand loops in cancer defeat this mechanism.
Cancer exploits RTKs through: activating kinase domain mutations (EGFR exon 19 del/L858R), gene amplification increasing surface receptor density (HER2, EGFR), autocrine ligand loops (VEGFA in clear cell RCC), ligand-independent constitutive activity (EGFRvIII deletion mutant in GBM), and oncogenic fusion proteins (EML4-ALK, RET fusions).
RTK-activating alterations define molecularly distinct cancer subtypes with dramatically different prognoses and treatment responses. EGFR-mutant NSCLC has 18+ month median PFS on osimertinib (vs ~6 months on chemotherapy). HER2+ breast cancer 5-year survival has risen from ~50% to >90% with HER2-directed therapy. ALK-rearranged NSCLC responds to lorlatinib with >75% response rates.
Receptor-directed therapy includes antibodies, kinase inhibitors, bispecific antibodies and antibody–drug conjugates, but each agent recognises a particular receptor state and has indication-specific evidence. Resistance can involve secondary target alterations, bypass signalling, altered drug delivery or histologic transformation; the pattern is heterogeneous and not inevitable on one timeline. Sacituzumab govitecan targets TROP2 and should not be interpreted as a general RTK-directed agent.
What makes HER2 different from other ErbB family receptors?
HER2 is unique in lacking a known activating ligand (it is an 'orphan' receptor) and in being the preferred heterodimerisation partner for EGFR, HER3, and HER4. HER2's kinase domain is constitutively active and always functions as the 'activator' kinase in the asymmetric dimer — making amplification extremely effective at driving signalling without requiring any ligand.
Why do anti-EGFR antibodies (cetuximab) fail in KRAS-mutant colorectal cancer?
Cetuximab blocks EGFR extracellular domain, preventing ligand binding and receptor activation. However, if KRAS is constitutively GTP-locked due to oncogenic mutation, KRAS signals continuously regardless of upstream EGFR status. Anti-EGFR therapy has no effect downstream of the mutation point — explaining mandatory RAS testing before prescribing cetuximab or panitumumab.
Understand sensitising EGFR mutations in NSCLC, how molecular testing is interpreted, and how T790M, C797S, MET amplification and other resistance mechanisms differ.
How HER2 gene amplification drives constitutive receptor signalling, how trastuzumab and antibody-drug conjugates exploit HER2 overexpression, and emerging HER2-low treatment strategies.
How KRAS mutations lock the EGFR→KRAS→BRAF→MEK→ERK cascade in constitutive activation, why KRAS was undruggable for 40 years, how G12C covalent inhibitors work, and combination strategies overcoming EGFR-mediated resistance.
Learn how different types of gene mutations — point mutations, deletions, amplifications, and fusions — drive cancer and inherited disease, with real examples from TP53, KRAS, and BRCA1.
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