The EGFR/HER Family: Dimerisation, Ligand Independence & Resistance
HER2 has no ligand. HER3 has no kinase. Together they are the most potent signalling pair in the family. That single fact explains most of what is strange about this pathway and all of what is strange about drugging it. Seven ligands feed four receptors, and the receptors do not act independently \u2014 they pair, and the identity of the pair decides which tyrosines are phosphorylated, which adaptors are recruited, and whether the signal runs to proliferation or to survival. EGFR holds a tethered, autoinhibited conformation until ligand extends its dimerisation arm, so it can be blocked by competing with the ligand. HER2 sits permanently open with nothing to compete against, which is why pertuzumab had to be aimed at the dimerisation arm instead. Click any protein for the matching Assay Genie antibody, biosimilar or ELISA kit.
One receptor with no ligand, one with no kinase. The HER family is usually drawn as four parallel receptors, and that drawing is the source of most confusion about it. HER2 binds nothing: its extracellular region is already in the extended, dimerisation-ready conformation that the others only adopt after ligand binding, so it is the preferred partner for everything else and cannot be blocked by ligand competition. HER3 has a pseudokinase domain and contributes essentially no catalytic activity \u2014 what it contributes is six docking sites for the PI3K regulatory subunit, more than any other family member. EGFR has none and must borrow Gab1 to reach PI3K at all. Put the two together and the HER2\u2013HER3 heterodimer pairs an unlimited dimerisation partner with the strongest PI3K recruiter in the family, which is why it is the most transforming pair known in this system and why NRG1 fusions are oncogenic on their own.
Epitope decides mechanism, not affinity. This map carries six antibodies as nodes rather than as footnotes, because the differences between them are mechanistic rather than incremental. Cetuximab, panitumumab and necitumumab all bind domain III and block the ligand site; they differ in isotype, so they differ in ADCC, and the comparison between chimeric IgG1 and fully human IgG2 is the cleanest way to ask how much of an anti-EGFR antibody's effect is Fc-mediated rather than blocking. Nimotuzumab was designed with deliberately intermediate affinity, so it only remains bound where EGFR density permits bivalent attachment \u2014 avidity rather than affinity does the targeting, and that is why it spares normal skin. Pertuzumab binds HER2 domain II, the dimerisation arm, which is the only way to drug a receptor that has no ligand, and is why it adds to trastuzumab rather than duplicating it. Patritumab attacks the catalytically dead partner instead of the driver.
The pathway defends itself at every level. ERK phosphorylates SOS1 and the receptor itself as a brake, so inhibiting ERK or MEK releases that brake and the signal rebounds \u2014 adaptive resistance appearing within days rather than months. Inhibiting mTOR relieves S6K suppression of IRS-1 and reactivates PI3K upstream. And the bypass band is the same lesson in a different register: amplified MET phosphorylates HER3 directly, restoring the survival arm while the EGFR antibody remains fully bound to a receptor the tumour no longer needs. AXL does it by expression change rather than mutation, which makes it invisible to sequencing. SHP2 is where these routes converge above Ras, which is exactly why it became a target: it closes several bypasses at once.
What this map is made of, precisely. Only one node \u2014 EGFR itself \u2014 carries a functional-grade In Vivo antibody, and it is the only blue dot on the page. This is a biosimilar map, and the biosimilar range happens to cover it unusually well: nine anti-EGFR antibodies against a single receptor, two on HER2, two on HER3 and one on MET, all supplied as research-grade biosimilars and all carrying their clinical identity in the tooltip rather than the In Vivo dot, which is reserved for the functional-grade range. Everything below the membrane \u2014 every adaptor, both kinase arms, the whole proliferative output \u2014 is measurable here and not blockable, which for a signalling map is the expected division. PI3K/AKT/mTOR, JAK/STAT and the IL-6 axis each have their own dedicated map in this library and appear here as entry nodes rather than being redrawn. For research use only; not for use in diagnostic or therapeutic procedures.
Every protein node links to a product — ELISA kit, In Vivo antibody or research antibody.