Tyrosine kinases and disease

 

 Tyrosine Kinases are involved in many, many cellular functions and as such can be highly associated with a variety of diseases. The receptor protein  tyrosine kinases have roles in cell growth, survival and differentiation and so dysfunction of any of these functions can result in tumour formation. There is much current research going in to the production of inhibitors of these kinases in the hope of alternative treatments to many cancers. Not only does inhibition of tyrosine kinases offer treatments for diseases directly resulting from a mutation in a tyrosine kinase but also any dysfunction of a pathway in which a tyrosine kinase is involved, as inhibition of the kinase results in inhibitionof the whole pathway.

 

 

 

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Epidermal Growth Factor Receptor and Cancer

 

Epidermal Growth Factor Receptor (EGFR) has been found to be associated with most common human solid tumours for example non-small cell lung, ovarian and cervical cancer. EGFR activity involves functions such as cell growth, proliferation, survival and angiogenesis and so it has a central role in all stages of tumour formation.

There are a variety of mechanisms that can lead to increased activity of EGFR:

• An excess of the ligand which activates the receptor

• High expression of the receptor at the membrane

• A mutation at the receptor that creates constitutive activity

• A failure to inactivate the receptor

 

One example of a cancer caused by an EGFR is breast cancer. Approximately 15-20% of breast cancer patients have increased expression of the Human Epidermal growth factor Receptor (HER2). It has been suggested that tumour formation occurs due to an increased activation of the PI-3 Kinase pathway. One target of PKB is P27kip1 which is an inhibitor the cell cycle regulator cdk2. When PKB phosphorylates P27kip1, it's prevents its entry into the nucleus and so stopping it from inhibiting cdk2 and the cell proliferates. As HER2 expression is increased there is more PKB and so more phosphorylation and there is no inhibition of cdk2 at all hence cell proliferation and tumour formation.

 

 

 Bcr-Abl fusion protein

 

An example of a cytoplasmic tyrosine kinase associated with cancer is the Abelson tyrosine kinase (Abl). Chronic Myeloid Leukaemia (CML) is a cancer which is characterised by an increase in growth of myeloid cells in the bone marrow which then accumulate in the blood. It is caused by a fusion of two genes: Abl gene and the Breakpoint Cluster Region (Bcr) gene.

The Abl gene which is found on chromosome 9, is translocated on to the Bcr gene on chromosome 22 creating a fusion chromosome known as the Philadelphia chromosome.

This fusion gene produces a fusion protein in which the tyrosine kinase activity of the Abl part is constitutively active. This then leads to uncontrolled cell growth and proliferation. On top of this Abl is usually responsible for entering the nucleus and inducing apoptosis but the fusion protein does not do this, contributing to its oncogenic effects.

 

 

 

Image courtesy of https://en.wikipedia.org/wiki/File:Bcrablmet.jpg and is free of any copyright restrictions

 

 Image courtesy of https://en.wikipedia.org/wiki/File:Philadelphia_chromosome.jpg and is in the public domain.

 

 

Treatments

 

There has been limited success in finding inhibitors of the tyrosine kinases, this is partly because, as well as all other protein kinases, they share a common catalytic domain and so it is difficult to produce specificity in drugs. However for the two examples above there are treatments available.

 

For HER2 expressing breast cancer there has been a monoclonal antibody produce which is now in clinical use. Trastuzumabs, better known as herceptin, acts by binding to the extracellular region of the HER2 receptor. This binding induces the cell to undergo arrest during G1 phase of the cell cycle and so decrease the proliferation. It is also thought to down regulate the HER2 receptor and suppress angiogenesis and has proved a very successful treament.

 

Glivec, a small molecule inhibitor, works as a treatment for CML. Glivec (STI- 571) binds to the Abl fusion protein and was the first drug developed that bound to a kinase specifically. The drug binds to the highly conserved ATP binding site and so is ATP competitive. However it also extends in to the kinase domain and actually switches the kinase into an inactive conformation. This mechanism probably explains why it is much more specific then inhibitors that bind the ATP site alone. Although it is relatively specific it also inhibits the c-kit kinases and is a treatment for gastrointestinal stromal tumours as well.

 

 

 Image courtesy of https://en.wikipedia.org/wiki/File:Glivec_400mg.jpg and is free of all copyright restrictions