Introduction to TKIs

Tyrosine kinase inhibitors are small molecules that are effective in the treatment of a wide variety of cancers. Here, we review tyrosine kinase inhibitors pharmacology – covering indications, mechanism of action, key adverse effects, and other important clinical pharmacology that you need to know.

Tyrosine kinases are enzymes that belong to the family of protein kinases. They phosphorylate the cell by transferring the phosphate group from ATP to cell proteins and hence regulates signal transduction and intracellular signaling. Tyrosine kinases are responsible for cellular activities like cell division, cell differentiation, cell migration, cell growth, cell metabolism and apoptosis in response to internal and external stimuli.

The tyrosine kinase receptors are free-floating monomers present on the cell membrane, having an intracellular and extracellular domain. The growth factor causes dimerization and activation of receptor monomers which, in turn, phosphorylates tyrosine kinase in the intracellular domain. There are many different types of tyrosine kinase receptors, the ones which are involved in anticancer effects are mainly VEGFR kinase, EGFR kinase, SRC family, Bruton tyrosine kinase, PDGFR kinase and ABL family.

All these drugs have a suffix –tinib, letting you know that they are small molecule inhibitors. We can classify tyrosine kinase inhibitors as follows:

BCR-ABL tyrosine kinase inhibitors

  • Imatinib
  • Dasatinib
  • Nilotinib
  • Bosutinib
  • Ponatinib

EGFR tyrosine kinase inhibitors

  • Gefitinib
  • Erlotinib
  • Lapatinib
  • Osimertinib
  • Neratinib
  • Vandetanib
  • Dacomitinib

VEGF receptor tyrosine kinase inhibitors

  • Sunitinib
  • Sorafenib
  • Axitinib
  • Lapatinib
  • Ponatinib
  • Cabozantinib

Bruton’s tyrosine kinase inhibitors

  • Ibrutinib
  • Zanobrutinib
  • Acalabrutinib

RTKIs

  • Pexidartinib

Normally, the activity of tyrosine kinase is short and reversible due to the action of protein tyrosine phosphatases. In cancer, usually tyrosine kinases or their pathways are activated by mutation, gene amplification or chromosomal translocation, resulting in increased growth of cancerous cells. Since these pathways regulate cell proliferation, its survival, migration and angiogenesis, tyrosine kinase inhibitor medicines serve as effective weapons against cancer.

Tyrosine kinase inhibitors work by blocking the tyrosine kinase from sending chemical messages to the cells that signals them to grow. They inhibit the effects of growth factors like EGF, VEGF, PDGF and others. They stop replication of cells and the formation of new blood vessels that provide nutrition and oxygen to the cancerous cells. On the oncogenic tyrosine kinases, tyrosine kinase inhibitors compete with the ATP binding site of the catalytic domain. They interfere with specific cell signaling pathways, therefore serving as targeted therapy often with fewer adverse effects compared to previous therapies.

Lapatinib is also a tyrosine kinase inhibitor but it also targets a protein called HER2 (human epidermal growth factor receptor-2). This protein is present in large amounts in breast cancer. Since HER2 helps the cells in their growth and division, lapatinib stops the activity of HER2.

Tyrosine Kinase Inhibitors Pharmacology

Drug Trade name Indications Side effects
Imatinib Gleevec Acute lymphoblastic
leukemia
Chronic eosinophilic
leukemia
Chronic myeloid
leukemia (Ph+)
Bone marrow disorders
Skin cancer
Gastrointestinal stromal
tumor
Congestive heart failure
Myalgia
Fluid retention
Periorbital edema
Dasatinib Sprycel Ph+ chronic
myelogenous
leukemia(CML)
Ph+ acute lymphoblastic
leukemia (ALL)
Pulmonary edema
Gastrointestinal
hemorrhage
Pericardial effusion
Dyspnea
Pleural effusion
Anasarca
Nilotinib Tasigna Ph+ CML QT prolongation
Difficulty in breathing
Arrhythmias
Bleeding Severe
diarrhea
Gefitinib Iressa Non-small cell lung
cancer
Acne-like rashes
Lung disease
Acute dyspnea
Cough
Erlotinib Tarceva Lung cancer
Pancreatic cancer
Conjunctivitis
Pruritis
Stomatitis
Xeroderma
Infections
Sunitinib Sutent Gastrointestinal stromal
tumor
Hepatotoxicity
Posterior reversible
encephalopathy syndrome
Holes in the gastrointestinal tract
Tachycardia
Heart failure
Sorafenib nexAVAR Giant cell tumors Severe liver injury
Abdominal pain
Tachycardia
Neutropenia
Lymphocytopenia
Anemia
Edema of eye
Fatigue
Increased lactate
dehydrogenase
Vandetanib Caprelsa Thyroid cancer QT prolongation
Torsades de pointes
Hypertension
Skin erythema
Hypocalcemia
Acne vulgaris
Proteinuria
Lapatinib Tykerb Breast cancer Hepatotoxicity
Diarrhea
Neutropenia
Acneiform rashes
Palmar-plantar
erythrodysesthesia

Clinical considerations

Here are some important clinical considerations about tyrosine kinase inhibitors pharmacology that you need to know:

  • Sunitinib, sorafenib, vandetanib and pazopanib metabolize through the liver by CYP 3A4. Therefore, caution should be exercised with coadministration of CYP3A4 inducers, as they may decrease the plasma concentration of tyrosine kinase inhibitors. Similarly, CYP inhibitors can increase toxicity risk.
  • Antiangiogenic drugs can cause an increase in blood pressure; an important consideration for patients with hypertension and other underlying conditions.
  • Nilotinib carries a black-box warning for cardiac complications – including an increased risk of QT prolongation, hypokalemia, and arrhythmias. Other drugs – such as vandetanib, sinitinib, and pazopanib, can also cause QT prolongation.

That completes our study of tyrosine kinase inhibitors pharmacology. Check back to our pharmacy blog soon for more content on TKIs and other important medicines used in the treatment of cancers.