Targeted therapies block the spread or growth of cancer by interfering with specific molecules or pathways involved in the growth and progression of cancer. The target molecule may be present in normal tissue, but is overexpressed or mutated in the cancer. These drugs can be more effective than cytotoxic chemotherapy as they are specific to the cancer.
Targeted therapy can be delivered orally or not. Small-molecule inhibitors are given orally. Although treatment is initiated and managed by a cancer specialist, ongoing therapy may not always need to be administered in an oncology setting and patients taking these drugs are increasingly being seen in general practice. Monoclonal antibodies are another type of targeted therapy for cancer. However, these drugs are given parenterally because they are proteins and would be destroyed by the gut.
BCR-ABL) inhibitors: Imatinib was one of the first targeted therapies to be developed for the treatment of chronic myeloid leukaemia. It blocks the BCR-ABL protein kinase which results from a chromosomal translocation (the Philadelphia chromosome) in chronic myeloid leukaemia. Imatinib inhibits the proliferation of leukaemia cells and results in durable responses in over 80% of patients. Imatinib is also active against gastrointestinal stromal tumours and certain types of acute leukaemia.
Epidermal growth factor receptor inhibitors: The epidermal growth factor receptor (EGFR)) exists on the outside of cells and is activated by growth factor ligands. Once activated, intracellular tyrosine kinase activity occurs and several signal transduction cascades are initiated which lead to cell proliferation. In many cancers the EGFR activity is increased due to mutations in the receptor or tyrosine kinase protein domains. EGFR tyrosine kinase inhibitors, such as erlotinib and gefitinib, act on the EGFR tyrosine kinase domain. They are used to treat advanced non-small cell lung cancers that have the EGFR mutation. Lapatinib inhibits the tyrosine kinase activity associated with EGFR and human epidermal growth factor receptor 2 (HER2)). The HER2 receptor is overexpressed in about 25–30% of breast cancers.
BRAF) and MEK) inhibitors: Other targeted drugs inhibit pathways that occur downstream of the EGFR receptor. Dabrafenib inhibits the activity of BRAF, an intracellular protein kinase of the RAF kinase family that drives cell proliferation and can be mutated in melanoma cells. Dabrafenib significantly improves progression-free survival (by approximately two months) in melanoma compared to standard chemotherapy.Trametinib inhibits the MEK pathway and has been combined with dabrafenib in an effort to reduce resistance to dabrafenib, and to reduce some of the adverse effects associated with BRAF inhibition.
Multi-targeted drugs including vascular endothelial growth factor inhibitors: Sunitinib, sorafenib and pazopanib are kinase inhibitors that affect multiple pathways involved in cancer cell growth. In addition to blocking tyrosine kinase pathways they block the vascular endothelial growth factor (VEGF)) protein which promotes angiogenesis. These drugs are active in a variety of cancers due to their diverse activity.
Carrington C. Oral targeted therapy for cancer. Australian Prescriber. 2015;38(5):171-176.