Introduction to signal transduction
One of the most common questions an oncologist hears from a pet owner is, "Why did my dog get cancer?" While it is often impossible
to provide a specific answer for a specific patient, our understanding of why cancer develops has grown exponentially in the
past decade. As are most things in the living organism, the causes are extremely complex, multifactorial, and still not completely
understood. One basis for understanding how a malignant cell develops comes from knowledge of the normal cellular processes
involved in cell division, growth, and differentiation. A critical process in the life of a cell is signal transduction, or
transmission of a signal from the outside of the cell to the inside. Cells need to respond to their environment, and signal
transduction is a major way in which the cell modulates what it does based on outside factors. Certain proteins found on the
cell surface can bind factors and then send a signal into the cell once bound. One such type of signal is sent biochemically
via phosphorylation of proteins in a cascade and can lead to cell proliferation, differentiation, and survival via their ultimate
effect on gene transcription. If this signaling becomes uncontrolled, cell growth can become unregulated and lead to tumor
development.
Tyrosine kinases
Tyrosine kinases (TKs) are a very important class of signaling proteins. They are found not only on the cell surface (these
are known as receptor tyrosine kinases [RTKs]), but also in the cytoplasm and the nucleus. In the normal cell, a growth factor
can bind to its TK receptor, which then becomes activated and passes on the signal internally via binding adenosine triphosphate
(ATP) and then adding phosphate groups to itself (autophosphorylation) and to other molecules farther down the pathway ("downstream").
At least 20 types of protein can be found on the cell surface that are included in the family of RTKs. Examples include Kit,
epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth
factor receptor (PDGFR). While TK signaling is critical for normal development and life processes, unregulated signaling can
lead to uncontrolled cell growth and survival and thus is one of the underlying causes of some types of cancer. The classic
example of TK dysregulation in human cancer is chronic myelogenous leukemia (CML). These cancer cells have a mutation that
causes chronic activation of a cytoplasmic kinase (Abl), which leads to chronic abnormal cell growth and survival of these
abnormal cells. In dogs, mutations in the RTK Kit, which lead to constant activation, have been found in 20% to 30% of mast
cell tumors (MCTs). Dogs with MCTs with Kit mutations have an increased chance of tumor recurrence and a decreased survival
time. Mutations in Kit have also been found in gastrointestinal stromal tumors (GISTs–previously called leiomyosarcomas on
histopathology). Inhibitors of these kinases, or tyrosine kinase inhibitors (TKIs), are a way to more directly target a cancer
cell. TKIs have been approved for treatment of certain types of cancer in humans and, recently, dogs.
Tyrosine kinase inhibitors
The most effective approach to blocking the signaling from RTKs has been to use small molecules that block the ATP binding
site of the kinase. With this blockage, TKIs prevent the kinase from phosphorylating and beginning the signaling cascade,
which can lead to an inhibitory/fatal effect on the cancer cell itself, or on the blood vessels that are feeding the cancer
cells. These TKIs are generally orally bioavailable.
Imatinib mesylate (Gleevec–Novartis) is one of the most successful TKIs in use. It was developed to target the Abl kinase
in humans with CML and has dramatically changed the survival rate of that disease: 90% of patients have progression-free survival
of at least 5 years. Gleevec binds the KIT kinase as well and has also shown excellent efficacy against human GISTs.
Sunitinib (Sutent–Pfizer) was developed to block new blood vessel growth (angiogenesis) and binds RTKs in the split kinase
family, including VEGFR, PDGFR, and Kit. Sutent has activity against a number of tumors, including those affecting the colon
and breast.
