Tyrosine kinase inhibitors (TKIs) are small molecule compounds that block the ATP binding site of the TK enzyme.16 Imatinib was the first TKI to be used in humans and inhibits the protein tyrosine kinases - BCR-ABL, PDGFR, and KIT.10, 11
Imatinib was developed to target the fusion protein BCR-ABL present on the Philadelphia chromosome in chronic myeloid leukaemia (CML). It acts by blocking the binding site of BCR-ABL thus preventing cell proliferation. Imatinib has been found to have application in the management of other malignancies as it also inhibits two other tyrosine kinases - PDGFR and KIT. This has led to the approval of imatinib in: 5
- gastrointestinal stromal tumours
- chronic myelomonocytic leukaemia
- aggressive systemic mastocytosis
- hypereosinophilic syndrome / chronic eosinophilic leukaemia
- dermatofibrosarcoma protuberans.
An emerging problem of imatinib therapy is the development of resistance. Imatinib failure results when there is reactivation of BCR-ABL mutations diminishing the binding of the drug.12 Second generation tyrosine kinases (such as dasatinib and nilotinib) have different binding characteristics. They have been found to be more potent and highly effective in the setting of imatinib failure.12
EGFR tyrosine kinase inhibitors
The epidermal growth factor (EGF) family of receptors comprises four closely related but distinct receptors:10, 17
The EGF family receptors are transmembrane glycoproteins that regulate cell growth, differentiation, and survival. 10, 12, 17 The EGFR-tyrosine kinase signal is strictly regulated in normal processes such as embryogenesis, organogenesis, and epithelial tissue repair. Events that can switch on EGFR-tyrosine kinase signaling extracellularly include ligand binding of EGFR and over expression of EGFR.10
Intracellular events can include:10
- over expression of EGFR
- cross communication between other receptors
- loss of regulatory mechanisms
- mutations of EGFR.
Several cancers have been identified that over express this receptor, resulting in more aggressive tumours with an increased tendency for invasion, metastases, and shortened survival.10, 12 These cancers include:
- head and neck
A number of monoclonal antibodies have been developed to block the extracellular domain:9
- EGFR-1 includes cetuximab and panitumumab in colorectal cancer
- EGFR-2 includes trastuzumab and was the first successful HER-2 targeted therapy in breast cancer.
Small molecule compounds have been developed that target the intracellular domain of EGFR. They inhibit phosphorylation of tyrosine kinase, preventing the message for cell division being sent to the nucleus.9
- Erlotinib inhibits EGFR-1 in lung and pancreatic cancer.
- Gefitinib inhibits a number of tyrosine kinases in lung cancer.
- Lapatinib blocks both EGFR-1 and 2 receptor kinases in breast cancer.
Identify a molecular targeted therapy used in cancer treatment, and describe the:
- mechanism of action
- indications for its use in clinical practice
- nursing care considerations.