Targeting the BCR–ABL tyrosine kinase in chronic myeloid leukemia as a model of rational drug design in cancer

Abstract

Many biological and clinical features of chronic myeloid leukemia make it as a paradigm of rational drug design in human cancer. Chronic myeloid leukemia was the first malignancy to be linked to a clear genetic anomaly, the Philadelphia chromosome and, at present, it is probably the best understood of all human malignancies. Studies of the disease pathology revealed that the molecular consequence of the Philadelphia translocation is a BCR–ABL chimeric gene, which encodes a constitutively active tyrosine kinase with wholesale range of biological activities. Animal models have validated the direct role of the BCR–ABL protein in malignant transformation and subsequent research confirmed that its enhanced tyrosine kinase activity is essential and sufficient for the leukemogenesis. The very existence of a single genetic abnormality, presented in essentially all patients with the disease, made it an effective target for molecularly designed therapeutic approaches for the disease. The advent of tyrosine kinase inhibitors, designed specifically to inhibit the tyrosine kinase activity of the BCR–ABL oncoprotein, represents one of the major innovations in cancer therapy and may serve as a model for, how discoveries of disease pathogenesis may be translated into the development of successful targeted therapies in cancer medicine.

Keywords::

• chronic myeloid leukemia
• targeted therapy
• tyrosine kinase inhibitors

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Notes

The T315I mutation gives rise to a highly resistant kinase and confers complete resistance to all of the tyrosine kinase inhibitors currently available for clinical use in CML.

Bold: Highly resistant; Nonbold: Resistant.

CML: Chronic myeloid leukemia.

CML: Chronic myeloid leukemia.