Kinase Inhibitors

Tyrosine kinase inhibitors (TKIs) are a class of chemotherapy medications that inhibit, or block, the enzyme tyrosine kinase. TKIs were created out of modern genetics- the understanding of DNA, the cell cycle, and molecular signaling pathways- and thus represent a change from general to molecular methods of cancer treatment. This allows for targeted treatment of specific cancers, which lessens the risk of damage to healthy cells and increases treatment success.

To understand how TKIs function, one must look to the cellular level. Receptor Tyrosine Kinases (RTKs) are a family of tyrosine protein kinases. RTKs span the cell membrane with an intracellular (internal) and extracellular (external) portion. The intracellular portion removes a phosphate group, a process called phosphorylation, from the coenzyme messenger ATP. The extracellular portion has sites to which signal sending proteins and hormones can bind. Many of these signaling binders are growth factors.

Growth factors are involved in the initialization and regulation of cell cycles. The type of growth factor determines its effects on the cell. There are three primary growth factors that relate to tyrosine kinase. The receptors of these growth factors are members of the RTK family. Epidermal growth factors (EGF) help regulate cell growth and differentiation. Platelet-derived growth factor (PDGF) regulates cell growth and development. Vascular endothelial growth factors (VEGFR) are involved in the creation of blood vessels.

The growth factors, and the kinases, act as though they are attached to an “on/off” switch. The removal of a phosphate group changes the shape and actions of the protein. This essentially “turns on” the cellular action (or actions). When the cellular action(s) is completed, the phosphate group is removed and that protein is “turned off”. This “on/off” process can become disrupted, often thanks to a mutated kinase, and actions can become unregulated. An unregulated RTK bound to EGF, for example, could lead to uncontrolled growth and division in the cell. The rapid cell growth could then lead to cancer. Mutations of RTKs often lead to oncogenes, which are genes that help turn a healthy cell into a cancerous cell.

Tyrosine kinase inhibitors treat cancer by correcting this deregulation. How this is done varies depending on the medication. Imatinib (brand name: Gleevac), for example, blocks a kinase gene from binding to ATP, preventing the phosphorylation that would benefit the cancerous cell and promote cell division. The medication gefinitib (Iressa) inhibits EGFRs, preventing that signal from being stuck “on” and creating uncontrolled proliferation.

Eight TKI medications, including imatinib and gefinitib, have been approved by the Food and Drug Administration for use in humans. One TKI, toceranib (Palladia), was recently approved for the treatment of cancer in dogs. The human medications may inhibit one or more tyrosine kinases. Erlotinib (Tarceva),Erlotinib like gefitinib, inhibits EGFR. Lapatinib (Tykerb) is a dual inhibitor of EGFR and a subclass called Human EGFR type 2. EGFR isn’t the only growth factor targeted. Sunitinib (Sutent) is multi-targeted, inhibiting PDGFR and VEGF.

Other tyrosine kinase inhibitors are more specialized. Sorafenib (Nexavar) targets a complex pathway that would lead to a kinase signaling cascade. Nilotinib (Tasinga) inhibits the fusion protein bcr-abl and is typically prescribed when a patient has shown resistance to imatinib.

More TKIs are currently in development, though the process is slow and more drugs end up being abandoned during clinical phases than get approved. Three TKIs are currently showing promise in clinical trials. Bosutinib targets abl and src kinases. Neratinib, like lapatinib, inhibits EGFR and Human EGFR type 2. Vatalanib inhibits both VEGFR and PDGFR.

Scientific research is being focused on TKIs because of their uniqueness compared to previous chemotherapy methods. All chemotherapy drugs seek to stop cells division and growth. They also attempt to kill cancerous cells without destroying the healthy cells. An inherent weakness in cancerous cells is that a failure of cell repair mechanisms is what turned the cells cancerous. The cell is therefore unable to repair damaged or changed DNA effectively.

Radiation therapy treatments interfered with the DNA to create a problem the cancer cell cannot repair, leading to cell death. This interference can be done by modifying the building blocks, the bases, by adding to them to prevent bonding. Or it may be done through mechanical processes that separate the strands of DNA. These methods are rather non-specific, both in terms of the cancers they treat and the cells the act upon. This means that healthy cells may also pay the price of treatment.

Destruction of healthy cells is one of the main problems with traditional chemo treatments. TKIs, however, are targeted in that the different types can be cancer-specific, acting upon pathways that have gone awry in the specific cancer. Furthermore, it is often a case that the kinase itself is slightly different from the normal version, meaning that the inhibitor can work specifically on cancerous cells. The only other current treatment that works in a similar way is using monoclonal antibodies, which can be used to target cancerous cells in preference over healthy ones.

The specificity of TKIs means there will be fewer side effects and less time in the hospital needed for the patient. The genetic basis for these cancers that can be treated with TKIs can now be screened effectively and early treatment is by far the most effective.