EGF Flashcards
Structure of EGF receptors?
Single pass transmembrane molecules!
Which ErbB molecules are not autonomous?
HER-2 (no known ligand) and HER-3 (cannot autophosphorylate). Leaves two functioning homodimers and a further six heterodimers!
Sequence of events in EGF binding?
Ligand binds to L1 and L2 (I and III), ligand-binding domains; get conformational change to expose dimerisation loop which is tethered between CR1 and CR2; forms dimers; get autophosphorylation of tyrosine residues in C terminal domain; effectors such as Grb1 are recruited and bind via SH2 domains to pTyr in C terminal domain.
EGFR components?
Has extracellular domain consisting of two ligand binding domains (I and III) and two cysteine rich domains (II and IV); transmembrane segment, juxtamembrane domain, kinase domain, and C terminal domain.
Two main downstream pathways of EGFR?
- Grb2 binds via SH2 domain; recruits the GEF SOS via the Grb2 SH3 domain to activate Ras; Ras dissociates GDP, binds GTP and activates Raf. This = MAPK/ERK pathway; transcription of MYC etc.
- Also P* of PI3K which, via PDK1 triggers PI3K/Akt pathway. This pathway includes mTOR and generally is anti-apoptotic.
Name of MAPK?
Mitogen-activated protein kinases; mitogens include things like EGF. Part of MAPK/ERK. Downstream of Ras/Raf.
Overcoming resistance with mTOR and EGFR?
mTOR is downstream of EGFR; some evidence that mTOR inhibitor resistance is partially regulated by signals that upregulate EGFR; targeting both could therefore inhibit resistance.
Three main ligands for EGFR?
EGF, TGFa, amphiregulin
Four ways that EGF signalling is implicated in cancer?
- Increased expression of ligands (EGF, TGFa)
- Mutations in effector proteins (e.g. BRAF and KRAS mutations leading to constitutive activity of MAPK/ERK pathway.
- Mutated receptor e.g. neu mutated in NSCLC leads to constitutive activity
- Receptors overexpressed and therefore hypersensitive to ambient signals
EGFR and prognosis generally?
A marker of poor prognosis; associated with decreased survival and increased metastasis in NSCLC, breast, CRC
Trastuzumab?
mAb to CR2 domain (IV) of HER-2; prevents dimerisation and causes ADCC. Indicated for HER-2 positive breast cancer in early and advanced setting, always alongside chemotherapy (taxane and anthracycline). In breast cancer, do IHC for expression; if +++ treat, if + ignore, if ++ then do FISH. Given as IV infusion, main AE is cardiotoxicity (must be wary of low EF); also get nausea, rash, flu-like.
Kadcycla (trastuzumab emtansine)?
Antibody-drug conjugate; directs
Kadcycla (trastuzumab emtansine)?
Antibody-drug conjugate; directs highly potent cytotoxic (covalently linked); delivered by receptor-mediated internalisation. Shown efficacy in Phase III RCTs over chemotherapy + lapatinib, and over trastuzumab alone, in early and advanced HER-2 positive breast cancer.
Pertuzumab?
Binds to EC domain II (CR1) of HER-2, thus preventing dimerisation. First in class “dimerisation inhibitor” of HER2 with HER3. Used alongside trasztumab and docetaxel in advanced HER-2 positive cancer, and same combination in neoadjuvant setting. Trial showed improved survival compared to placebo in combination with above drugs in MBC.
Cetuximab?
Binds to EGFR. mAb. Competitively inhibits L2 (III) this preventing ligand binding. Indicated in advanced CRC (if EGFR+ve) either in combination with chemotherapy or as a single agent, and in metastatic NSCLC, and head and neck.Unlike trastuzumab, given if any EGFR positivity on IHC. Patients stratified for RAS mutation (53% of MCRC have K-RAS mutation); if WT then good efficacy, if have mutations in K-RAS (usually exon II) or Raf then not treated. May be NRAS too: old test just looked at exon II of KRAS but now study exons in NRAS and more in KRAS.
