Trastuzumab (Herceptin) is used in treatment of:
HER2 proto-oncogene ERBB2 located chromosome 17q12 encoding 185 kDa receptor tyrosine kinase member EGFR family characterized by extracellular cysteine-rich domains, single transmembrane helix, and intracellular kinase domain. Amplification in 15 to 20 percent invasive breast carcinomas leads to overexpression up to two million receptors per cell versus normal 20,000, facilitating ligand independent homodimerization and heterodimerization with HER3 bound to neuregulin, triggering transphosphorylation of tyrosine residues creating docking sites for Shc, Grb2, p85 subunit of PI3K. Downstream PI3K-AKT-mTOR pathway inhibits BAD promoting survival plus cyclin D1 driving proliferation, MAPK cascade induces transcription of EGR1. Trastuzumab humanized IgG1 generated by grafting murine CDRs onto human framework binds domain IV juxtamembrane region near transmembrane spanning, sterically hindering metalloprotease ADAM10 cleavage that would release active extracellular domain and preventing dimerization interface exposure. Additional actions include antibody-dependent endocytosis reducing surface density, suppression of shed ECD, blockade of downstream signaling, and recruitment of NK cells for ADCC. Combined with paclitaxel or docetaxel improves disease-free survival by approximately 50 percent. Companion diagnostic immunohistochemistry scores 3+ or fluorescence in situ hybridization ratio above 2.0 identifies HER2-positive breast cancer candidates before therapy.
Ref: Slamon et al NEJM 2001 344:783 HER2 trastuzumab domain IV; Harari & Yarden Oncogene 2000 HER2 dimer PI3K signaling.