Kinases are proteins that speed up chemical reactions in our bodies. They play a crucial part in many of our bodies’ essential functions. They help our cells divide and survive, play an important role in metabolism and immunity, as well as many other functions. However, sometimes kinases can become too active. High amounts of kinases can be found in some cancers. In these cases, kinases can help cancer cells grow and survive. This is why kinase inhibitors are important, as they stop the kinases from functioning in an abnormal way and may prevent cancers from growing and spreading.

What are kinases?

A kinase is a type of enzyme that adds a phosphate group to other biological molecules, such as proteins, lipids, or nucleotides. Adding a phosphate group to biological molecules regulates their activity. This process of adding a phosphate group to another molecule is known as phosphorylation. Kinases take this phosphate group from high-energy molecules such as adenosine triphosphate (ATP) or guanosine triphosphate (GTP). Kinases are precise as they only add phosphate groups to the specific molecule they target.¹ Most kinases are protein kinases. As the name suggests, they phosphorylate proteins. We have around 500 different protein kinases working in our bodies.² These kinases have been shown to phosphorylate more than two-thirds of the over 20,000 proteins expressed in the human genome.³ Protein kinases phosphorylate specific amino acids in proteins: serine, threonine, and tyrosine. The majority of phosphorylation by kinases is on serine amino acid residues (86.4%), followed by threonine (11.8%), and only around 1.8% phosphorylation is on tyrosine residues.³ 

The large majority of protein kinases (around 80%) phosphorylate both serine and threonine and are called serine/threonine kinases. Kinases that phosphorylate tyrosine amino acid residues are called tyrosine kinases. There are also dual-specificity kinases that can phosphorylate all three amino acid residues.⁴ Phosphorylation can either activate or inactivate specific proteins. This can then affect the functions of other proteins that they would typically interact with (a process known as cell signalling). Because of this, kinases play a crucial role in cell division and growth, cell death, protein synthesis, development, and ageing.³ 

As kinases have such an important role in our bodies, it is not a surprise that they are also important in disease. This includes conditions such as cancer, inflammation, immunological diseases, neurological diseases, and metabolic diseases, as well as viral, fungal, and parasitic infections.²

Tyrosine kinases

Despite making up a relatively small group of total kinases, tyrosine kinases are among the most well-studied kinase groups.² There are two classes of tyrosine kinases: receptor tyrosine kinases (RTK) and nonreceptor tyrosine kinases. 

RTK sit in the membrane of cells and can be activated by growth factors (molecules that control cell growth). This group includes well-known kinases such as vascular endothelial growth factor receptors (VEGFR), platelet-derived growth factor receptors (PDGFR), and the insulin receptor family. 

Meanwhile, nonreceptor tyrosine kinases are found inside the cell and are made up of nine families: Abl, Ack, Csk, Fak, Fes/Fer, Jak, Src, Syk/Zap70, and Tec.⁵

Sometimes tyrosine kinases can mutate or can be overexpressed, which can lead to increased activity of the kinase. In turn, this can lead to uncontrollable cell growth and proliferation which is typical of cancers.⁶ Abnormal activity of tyrosine kinases has been observed in many different cancers, including lung, breast, kidney, bladder, thyroid and gastrointestinal cancers as well as some types of leukaemia.⁶

Tyrosine kinase inhibitors

Tyrosine kinase inhibitors (TKIs) are a group of pharmacological therapies which are a form of targeted therapy. TKIs block tyrosine kinase from phosphorylating other proteins. This disrupts the cell signalling pathway that promotes cell growth and proliferation.⁵ This can be useful in cancer treatment as it reduces the rate of cancer cell growth. Tyrosine kinases have the highest percentage of FDA-approved small molecule inhibitors amongst all kinase groups, with almost 50% of tyrosine kinases having an FDA-approved inhibitor available.² 

What cancers can be treated with TKIs?

There are over 50 FDA-approved inhibitors of tyrosine kinases.⁵

The FDA-approved TKIs can be used to treat many different cancers, including but not limited to:⁷

• Thyroid cancer
• Chronic myeloid leukaemia
• Lung cancer
• Kidney cancer
• Acute lymphoblastic leukaemia
• Chronic lymphocytic leukaemia
• Colorectal cancer
• Gastrointestinal stromal tumour
• Liver cancer
• Soft tissue sarcoma
• Breast cancer
• Melanoma

What are some common TKIs?

Axitinib (Inlyta)

A VEGFR inhibitor prevents cancers from growing new blood vessels, which provide nutrients and oxygen needed for the cancer to grow. 

Axitinib is used to treat a type of kidney cancer (called renal cell carcinoma) which has metastasised to other tissues/organs.

Dasatinib (Sprycel)

A dual inhibitor of Abl and Src-family tyrosine kinases. 

Dasatinib is used to treat chronic myeloid leukaemia. It can also be used to treat acute lymphoblastic leukaemia if other treatments do not work.

Erlotinib (Tarceva) 

Erlotinib is an EGFR inhibitor. It is used to treat non-small cell lung cancer and pancreatic cancer.

Imatinib (Glivec) 

Imatinib is a PDGFR, BCR-ABL and c-KIT inhibitor. 

It is used to treat chronic myeloid leukaemia and acute lymphoblastic leukaemia. 

Imatinib can also be used in the treatment of other blood disorders such as myelodysplastic, myeloproliferative conditions, advanced hypereosinophilic syndrome, and chronic eosinophilic leukaemia. 

It can also be used to treat gastrointestinal stromal tumours.

Nilotinib (Tasigna) 

Nilotinib is a BCR-ABL tyrosine kinase inhibitor used to treat chronic myeloid leukaemia.

Pazopanib (Votrient) 

Pazopanib is a VEGFR, PDFGR and c-kit inhibitor used to treat advanced kidney cancer.

Sunitinib (Sutent) 

Sunitinib is a PDGFR, VEGFR, KIT and RET inhibitor used to treat gastrointestinal stromal tumours, renal cell carcinoma and pancreatic neuroendocrine tumours.

Benefits of TKIs

Using TKIs is highly beneficial if you have cancer because it is a targeted therapy. This means that it targets and kills cancer cells without damaging healthy cells. TKIs are used successfully to treat many different types of cancers. Additionally, TKIs can be used when other therapies do not work or when the cancer recurs (comes back after treatment) or when it metastasises (spreads to other tissues/organs).

Limitations of TKIs

Sometimes cancer cells can be resistant to TKI. They can be resistant to TKI to begin with (primary resistance) or develop resistance after initially responding to treatment (secondary resistance).⁷ Kinases can become resistant to treatment because of mutations that prevent the inhibitor from working. For example, BCR-ABL tyrosine kinase was shown to have around 50 different mutations that can cause resistance to its inhibitor imatinib.⁷

Potential side effects of TKIs

As with any other drug, TKIs also have potential side effects, some of which include:⁵

• Fatigue
• Fever
• Chills
• Weight loss or gain
• Abdominal pain
• Diarrhoea
• Constipation
• Nausea/vomiting
• Hypertension (high blood pressure)
• Hypotension (low blood pressure)
• Thrombosis
• Facial swelling
• Eczema
• Skin rash
• Proteinuria (high level of protein in your urine)
• Headaches
• Dizziness
• Cognitive impairment

How do you take TKIs?

Almost all TKIs are effective when taken orally.⁵ Each person differs in how they respond to drugs. The correct dosage for you will need to be determined by your doctor. 

There are a few factors that might affect how effective TKIs are. Interactions with other drugs, food, and how well your liver and kidneys metabolise drugs can all affect the effectiveness of TKIs.⁵

It is very important that you adhere to your treatment for it to be effective. This means that you should:

• Take the correct dose of TKI
• Make sure that you take your medication at the correct time
• Do not miss any doses
• Do not take an additional dose
• Follow the advice of your doctor on how to take this medication, such as with food or a glass of water
• Do not take it with any food or medications that might affect how the TKI works

Summary

Phosphorylation of proteins by kinases plays an important role in regulating many different biological functions in our bodies. Kinases are crucial for our survival, however, sometimes the activity of kinases can go wrong and cause diseases such as cancer. Tyrosine kinases are commonly targeted for cancer treatments. Many different tyrosine kinase inhibitors have been successful in treating different types of cancers. One of the main benefits of TKIs is that they are targeted treatments that kill cancer cells, leaving healthy cells untouched. However, as with any other drug TKIs are not always effective in treating cancers. Sometimes cancer cells can be resistant to treatments by TKIs. Additionally, there are some common side effects of TKIs, including fatigue, fever, headaches and nausea. In these cases, a different TKI or medication might be a better option for you.