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Page 2 of 19 Cordover et al. J Cancer Metastasis Treat 2020;6:45 I http://dx.doi.org/10.20517/2394-4722.2020.101

INTRODUCTION
Cells within multicellular organisms depend upon complex ways of communicating with their surroundings
and other cells and tissues. An important method by which cells communicate is by responding to signals
from extracellular stimuli. Growth factors are small extracellular ligands that transmit signals between cells
and their environment. They can control cell function by binding to transmembrane receptors, activating
a myriad of different intracellular signaling pathways. Growth factors commonly bind to the receptor
tyrosine kinase family of transmembrane receptors (RTKs). RTKs have an extracellular domain that binds
to ligand, a transmembrane domain, and an intracellular domain that has tyrosine kinase activity. Once
bound to ligand, the RTKs dimerize, and transphosphorylate on tyrosine residues. This usually leads to
binding of adapter proteins to the phospho-tyrosine residues, leading in turn to a cascade of events within
[1]
the cell . This includes activation of GTP binding proteins, a cascade of serine/threonine phosphorylation
events, and translocation of certain proteins to the nucleus. Ultimately this can lead to the regulation of
transcription factors which in turn result in changes in gene expression patterns. The result is the regulation
[2]
of genes that control cell growth, differentiation, survival, and function . In order to understand how
normal cell function and communication is regulated, it is critical to understand how those intracellular
events occur in normal cells.

In addition to their important roles in controlling normal cell fate, it is also important to understand the
roles that signaling pathways play in cancer. Intracellular signaling pathways are often improperly regulated
[3]
in cancer . As a result, cancer cells often become independent from their control by extracellular stimuli.
Instead, they can gain the ability to grow, proliferate, and survive, without external regulation. This is
an important feature of many cancer cells, and one that is important to understand in order to develop
individualized treatments.

Understanding which intracellular signaling proteins are most important for controlling cellular behavior
is important for understanding the molecular basis of cancer. There are multiple types of extracellular
stimuli and intracellular signaling pathways that are important for controlling cell growth. These include
not only pathways regulated by RTKs, but also pathways that are regulated by other types of receptors such
as trimeric G protein coupled receptors and cytokine receptors. The study of RTKs has taken a prominent
role in studying cancer. This is in part due to being linked to the Ras family of proteins, which are mutated
in a large percentage of cancers . Furthermore, multiple components of RTK activated signaling cascades
[4]
have been linked to cancer when they are aberrantly regulated. In this review we will focus on the signaling
pathways that are mediated by RTKs, which have been implicated in cancer when improperly regulated.
While the number of different pathways that are associated with cancer is large, we will focus on several
RTK regulated pathways in this review, and we will discuss their importance in cancer research. We then
discuss some of the drugs and drug candidates that are designed to target signaling proteins within these
pathways.

MITOGEN-ACTIVATED PROTEIN KINASE PATHWAY
The mitogen-activated protein kinase (MAPK) signaling pathway was discovered over 30 years ago. It
is one of the most well studied intracellular signaling pathways and it often serves as a model for RTK
activated signaling pathways. The MAPK pathway is frequently implicated in cancer and serves as an
important target for cancer therapies. The MAPK signaling cascade plays several key physiological roles in
[5]
healthy cells. Specifically, MAPKs mediate cellular growth, proliferation, and survival processes . MAPK
operates by modulating transcription factors, which in turn leads to regulation of gene expression in
[6]
response to extracellular signals . Abnormal MAPK signaling is shown to be associated with several types
of cancer such as breast cancer, prostate cancer, colorectal cancers, melanoma, and leukemia. Dysregulation
of MAPK signaling in cancer is associated with evasion of apoptosis, uncontrolled cell proliferation, and
[7]
resistance to chemotherapy and targeted therapies .