The Oncogenic Protein, Breakpoint Cluster (BCR)-Abelson Kinase (ABL) and Chronic Myelocytic Leukemia (CML): Insight Into the Drug Resistance Mechanisms and Approaches for Targeting BCR-ABL in CML

The discovery of the breakpoint cluster ( bcl )-Abelson kinase ( abl ) oncogene was one of the most important milestones for elucidating the pathophysiology of chronic myeloid leukemia (CML). Numerous studies have shown that due to various mutations, it has been difficult to find drugs that maintain significant efficacy over an extended period of time. The resistance of the BCR-ABL protein to pharmacotherapy is primarily due to point mutations and gene amplification, as well as a number of BCR-ABL—independent mechanisms. Tyrosine kinase inhibitors (TKIs), such as imatinib, have been shown to have significant efficacy in certain CML patients. However, the development of a mutation in the gate keeper region of BCR-ABL protein, “T315I,” significantly decreased or abrogated the clinical efficacy of certain TKIs. In this chapter, we discuss (1) the most common resistance mechanisms that occur in the BCR-ABL protein in CML patients and (2) the approaches that have been developed over the last two decades to inhibit the function of the BCR-ABL protein.