Trastuzumab is a recombinant humanized IgG1 monoclonal antibody to the human epidermal growth factor receptor 2 (HER2) that is administered intravenously for the treatment of HER2 positive breast cancer (adjuvant therapy), metastatic HER2-positive breast cancer and HER2 positive gastric cancer. HER-2 is over expressed in these cancer cells and therefore trastuzumab targets these cancer cells over normal cells. The HER-2 receptor is a transmembrane tyrosine kinase receptor that consists of an extracellular ligand-binding domain, a transmembrane region, and an intracellular or cytoplasmic tyrosine kinase domain. HER-2 forms heterodimers with other EGFR proteins such as HER-1, HER-2 or HER-4 when they bind to ligands or may form homodimers with other HER-2 proteins. Following dimerization, transphosphorylation/ autophosphorylation of the tyrosine residues on the cytoplasmic domain of these receptors occurs. This activates a number of intracellular signaling pathways such as the raf/MAPK pathway, PI3K/akt pathway and PLC/PKC pathway. The activation of these pathways recruits nuclear factors that regulate genes involved in cell-cycle progression, proliferation, growth and survival. Trastuzumab binds to the extracellular domain of HER-2 and prevents dimerization. Inhibiting dimerization prevents the activation of the downstream intracellular signaling cascades initiated by the HER proteins. This therefore prevents the gene regulation necessary to promote cell-cycle progression, proliferation, growth and survival. Nuclear transcription affected by these pathways cannot occur, and therefore essential proteins are not produced. This causes cell cycle arrest and suppresses cell growth and proliferation and eventually the cancer cell undergoes apoptosis. Side effects such as headache, chills, cough, back pain, weakness and fatigue, upper respiratory symptoms including rhinitis and pharyngitis, angioedema, cardiotoxicity, anaphylaxis and GI disturbances including nausea, vomiting, abdominal pain, diarrhea.

Trastuzumab Pathway (New) References