Receptor tyrosine kinase activation
Growth-factor receptors are antennas on the cell surface that pair up when a signal lands and switch on the growth relays inside. Cancers mutate, multiply, or fuse these antennas so they broadcast 'grow' with no signal at all. Most targeted drugs, antibodies and ADCs start here.
Ligand binding (EGF, HGF, FGF, NRG, SCF, PDGF, VEGF) dimerises RTKs, trans-autophosphorylating tyrosines that recruit SH2/PTB adaptors: GRB2-SOS to RAS-MAPK, p85 to PI3K-AKT, PLCγ, SRC, STAT3/5, and CBL for ubiquitin-mediated downregulation. Oncogenic activation: kinase-domain mutations (EGFR L858R/exon 19, exon 20 insertions; FLT3-ITD; KIT exon 11; HER2), extracellular-domain truncation (EGFRvIII), amplification (HER2, MET, FGFR1/2), fusions (ALK, ROS1, RET, NTRK, FGFR2/3, with dimerisation domains that pair the kinase constitutively), autocrine loops, and PTPN11 or CBL loss. Drug classes: reversible and covalent TKIs (with resistance via gatekeeper/solvent-front mutations such as EGFR C797S, ALK G1202R), antibodies that block ligand or receptor and recruit Fc effectors (trastuzumab, cetuximab), bispecifics (amivantamab EGFR×MET, zanidatamab HER2×HER2), and ADCs that use the receptor as a delivery address regardless of signalling (T-DXd on HER2-low). Bypass via a parallel RTK (MET amplification under EGFR blockade, HER3 upregulation) is the classic escape.
In one picture
Two halves of a walkie-talkie that only transmit when clipped together by a signal from outside. Cancer glues them together (fusions, mutations) or installs hundreds of extra sets (amplification), so the room is full of shouted 'grow' orders. TKIs pull the battery, antibodies tape over the microphone, ADCs use the aerial as a mailing address for poison.
Diagram
top- TKIs by driver: osimertinib (EGFR), lorlatinib/alectinib (ALK), selpercatinib (RET), larotrectinib/entrectinib (NTRK), capmatinib/tepotinib (MET), imatinib (KIT/PDGFRA/BCR-ABL), zongertinib (HER2)
- Antibodies: trastuzumab/pertuzumab (HER2), cetuximab/panitumumab (EGFR); bispecifics amivantamab (EGFR×MET), zanidatamab, zenocutuzumab (HER2×HER3)
- ADCs use the receptor as an address: T-DXd, T-DM1, patritumab deruxtecan (HER3), telisotuzumab vedotin (MET)
- Combining with MET or downstream inhibitors closes bypass routes
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