Biomedical Engineering Reference
In-Depth Information
benefits of these agents in unselected patients with advanced NSCLC
have been modest, driving efforts to identify biomarkers to define
subpopulations of patients with NSCLC most likely to benefit from
these agents. This chapter will review the status of this predictive
biomarker research for the EGFR inhibitors erlotinib, gefitinib, and
cetuximab, which are currently in clinical use for the treatment of
NSCLC.
6.2
The Epidermal Growth Factor Receptor
Family
The epidermal growth factor receptor (EGFR) family consists of
four members: EFGR, Human epidermal growth factor receptor-2
(HER2), HER3, and HER4. All members of the EGFR family contain an
extracellular ligand binding region, a membrane spanning region and
cytoplasmic region that possesses tyrosine kinase activity. The binding
of a ligand to the receptor leads to the formation of either homo- or
heterodimers between the members of the epidermal growth factor
receptor family and activation of tyrosine kinase activity.
2
This leads
to the binding of adenosine triphosphate (ATP) and phosphorylation
of the cytoplasmic component of the kinase. This phosphorylation
event allows adaptor proteins to interact with the receptor and
initiate the downstream signaling pathways
2
(see Fig. 6.1). Without
ligand, the EGFR receptor is found in a closed conformation with the
dimerization interface blocked. Unlike EGFR, HER2 has a different
extracellular region and has a fixed conformation, which results in
permanent exposure of the dimerization domain.
3
In addition, HER2
is unique among the receptor family in that it binds none of the
potential EGF ligands. As a result, it appears that its primary role
in the pathway is to form heterodimers with the other receptors.
4
HER3 also plays a distinct role in the HER family signaling network.
Although it is kinase inactive and therefore incapable of initiating
downstream signaling pathways on its own, HER3 can dimerize with
other receptors, particularly HER2, for potent cellular signaling.
Evidence is growing to show that the transactivating nature of HER3
is an essential aspect of oncogenic function of the related receptors
HER1/EGFR and HER2.
