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Table 1: Approved molecular targeted drugs in advanced gastro-intestinal tumors
Primary cancer site Targets Drugs OS (month) Reference
GC HER-2 Trastuzumab 13.8 (fi rst-line) [51]
VEGFR-2 Ramucirumab 9.6 (second-line) [53]
CRC VEGF Bevacizumab 20.3 (fi rst-line) [63]
Afl ibercept 13.5 (second-line) [84]
VEGFR, BRAF, KIT, RET, PDGFR Regorafenib 6.4 (third-line) [81]
EGFR Cetuximab 24.9 (fi rst-line) [75]
Panitumumab 26.0 (fi rst-line) [78]
HER2: Human epidermal growth factor receptor 2; VEGFR-2: Vascular endothelial growth factor receptor-2; VEGF: Vascular endothelial
growth factor; VEGFR: Vascular endothelial growth factor receptor; BRAF: V-Raf murine sarcoma viral oncogene homolog B1; KIT: Mast/
stem cell growth factor receptor; RET: Rearranged during transfection; PDGFR: Platelet-derived growth factor receptor; OS: Overall
survival; EGFR: Epidermal growth factor receptor; CRC: Colorectal cancer; GC: Gastric cancer

plays an important role in the growth and spread of than one signaling pathway or blocking multiple targets
[1]
cancers. Neovascularization promotes tumor growth within a single pathway may be necessary to effectively
by supplying nutrients, oxygen and growth factors that suppress cancer growth.
promote tumor cell proliferation. [2,3] VEGF was fi rst Phosphatase and tensin homolog-phosphoinositide
isolated in 1983 as a factor that increases vascular 3-kinase-AKT-mammalian target of rapamycin
[4]
permeability in tumors. The VEGF family of proteins
comprises VEGF-A, -B, -C, -D and -E, and structurally pathway
resembles the platelet-derived growth factor (PDGF) Phosphoinositide 3-kinases (PI3Ks) are a family
and placenta growth factor (PLGF) families of of lipid kinases that phosphorylate the 3’-hydroxyl
proteins. These growth factors bind selectively, group of phosphoinositides with the conversion
but with different affi nity, to at least fi ve distinct of phosphatidylinositol-4, 5-biphosphate to
receptors. [5-7] Many cytokines and growth factors, phosphatidylinositol-3, -4, 5-trisphosphate (PIP3). PIP3 is
including PDGF, tumor necrosis factor, transforming a critical second messenger that activates protein kinase
growth factor (TGF)-α, TGF-β, fi broblast growth B (AKT) through phosphorylation. Once activated,
factor (FGF)-4, keratinocyte growth factor/FGF-7, EGF, phospho-AKT phosphorylates up to 100 other proteins,
interleukin (IL)-1α, IL-1β, IL-6 and insulin-like growth including the mammalian target of rapamycin (mTOR),
factor (IGF)-1, are involved in upregulating VEGF which is part of the mTOR complex (mTORC) 1 and
gene expression. Overexpression of VEGF has been mTORC 2. [21,22] The activation of mTOR increases cellular
[8]
associated with increased microvessel density, tumor proliferation and survival and decreases apoptosis. In
invasion, metastasis and thus with poor prognosis in normal tissue, this pathway is negatively regulated
many types of cancers. [9] by the tumor suppressor phosphatase on chromosome
Epidermal growth factor receptor pathway 10 (phosphatase and tensin homolog), which targets the
lipid products of PI3K for dephosphorylation. [23]
The EGFR family consists of four homologous receptors:
The EGFR (ErbB1/EGFR/HER-1), ErbB2 (HER-2/neu), Ras-Raf-MEK-extra-cellular-signal-regulated
ErbB3 (HER-3) and ErbB4 (HER-4). EGFR is a 170 kinase pathway (MAPK pathway)
[10]
kDa cell surface tyrosine kinase (TK) transmembrane The Raf/ mitogen-activated protein kinase (MAPK)/
receptor that initiates signaling cascades leading to cell extra-cellular-signal-regulated kinase (ERK) pathway
proliferation, motility, adhesion, invasion, cell survival is an important pro-survival signaling pathway, that
[11]
and angiogenesis. Mutation in the TK domain of the is, primarily involved in cell growth and survival
EGFR gene has been found in several types of cancers and regulation of cellular differentiation. This
and has become a therapeutic target in non-small cell lung pathway transduces extra-cellular signals from
[12]
cancer. Overexpression and/or amplifi cation of HER-2 membrane-bound TK receptors, such as EGFR,
has been observed in various cancers, [13-15] including VEGF receptor (VEGFR), IGF receptor (IGFR),
breast, esophageal and GCs at 7-34% frequency, [16,17] and hepatocyte growth factor receptor (c-MET) and PDGF
several studies have shown that HER-2 is an important receptor (PDGFR), to the nucleus. Binding of growth
[18]
biomarker and a key driver of tumorigenesis. factors results in receptor phosphorylation, which
Therefore, blockade of the EGFR family should lead activates an adapter molecule complex. This sequence
to the inhibition of cell growth, thereby constituting an in turn activates the Raf/mitogen/extra-cellular protein
effective anti-cancer therapy. However, cross-talk kinase (MEK)/ERK pathway, which triggering a cascade
[19]
between the various ErbB receptors that may induce of specifi c phosphorylation events. Within this
[24]
drug resistance has been demonstrated. Because the pathway, the small GTPase Ras and the serine/threonine
[20]
[25]
intra-cellular space is vastly complex, targeting more kinase Raf are the key signal regulators. Intermediate
164 Journal of Cancer Metastasis and Treatment ¦ Volume 1 ¦ Issue 3 ¦ October 15, 2015 ¦