Biomedical Engineering Reference
In-Depth Information
6
Unlike the Ras pathway, EGFR
activation of the PI3K pathway requires only the presence of HER3
and is not dependent on adaptor proteins.
progression and cellular proliferation.
Interaction with PI3K
leads to phosphorylation of phosphatidylinositol 4,5-diphosphate,
resulting in phosphatidylinositol 3,4,5-triphosphate. This molecule
then activates of Akt and other downstream effector pathways
controlling cell proliferation and survival.
2
7
This results in increased
cell growth, apoptosis resistance, increased tumor invasion, and cell
migration.
8
In addition to the above pathways, EGFR has the ability to
regulate signal transducers and activators of transcription (STAT)
and sarcoma kinase (Src) pathways through the Janus kinase (JAK).
STAT proteins have been implicated in oncogenesis and tumor
progression while Src can cause increased EGFR signaling and
resistance to EGFR-targeted therapy.
9,10
6.4
EGFR Inhibitors for the Management of
NSCLC
Two major classes of EGFR-targeted therapies that have entered
clinical practice are the anti-EFGR monoclonal antibodies (MoAbs),
cetuximab (Bristol-Myers Squibb) and panitumumab (Amgen),
and EGFR-specific tyrosine kinase inhibitors (TKIs), erlotinib
(OSI Pharmaceuticals) and gefitinib (AstraZeneca). The MoAbs
bind to the extracellular domain of EGFR when it is in the inactive
configuration and compete with EGF receptor binding by occluding
the ligand-binding region. By doing so, receptor dimerization and
activation of the tyrosine kinase domain is prevented.
11
Anti-EGFR
MoAbs recognize EGFR exclusively and represent a highly selective
treatment. In contrast, TKIs compete reversibly with ATP for binding
to the intracellular tyrosine kinase catalytic domain. By inhibiting
the binding of ATP, the EGFR TKIs prevent phosphorylation of
the cytoplasmic kinase domain and the initiation of downstream
signaling. Unlike the MoAbs, the TKIs have the ability to inhibit
other growth factor receptor tyrosine kinases, potentially leading to
a greater range of side-effects with their usage.
12
EGFR inhibitors have been evaluated in phase III randomized
clinical trials in the curative and palliative setting (Table 6.1);
however, currently, these agents have only been shown to prolong
