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Pathway Description
Dasatinib Inhibition of BCR-ABL Action Pathway
Homo sapiens
Drug Action Pathway
Created: 2017-08-16
Last Updated: 2023-09-13
Dasatinib is a tyrosine kinase inhibitor used to treat chronic myelogenous leukemia (CML), a cancer characterized by increased and unregulated growth of white blood cells in the bone marrow and the accumulation of these cells in the blood. The cause of CML pathophysiology is the BCR-ABL fusion protein - the result of a genetic abnormality known as the Philadelphia chromosome in which Abelson Murine Leukemia viral oncogene homolog 1 (ABL1) translocates within the Breakpoint Cluster Region (BCR) gene on chromosome 22. BCR-ABL is a cytoplasm-targeted constitutively active tyrosine kinase that activates several oncogenic pathways which promote increased cell proliferation and survival including the MAPK/ERK Pathway, the JAK-STAT Pathway, and the PI3K/Akt pathway. Dasatinib is considered a second generation BCR-ABL inhibitor (Imatinib being the progenitor) that inhibits BCR-ABL activity by binding a highly conserved ATP binding site to effectively lock the tyrosine kinase in an inactive conformation. As a result, phosphate is unable to be transferred from ATP to activate oncogenic signalling cascades. For greater detail, refer to the pathway titled BCR-ABL Action in CML Pathogenesis. Dasatinib is able to bind ABL with greater affinity than Imatinib, partly owing to its ability to recognize multiple states of the enzyme. It is therefore administered to patients with Imatinib resistance. Notably, Dasatinib is ineffective against the T315I mutation in BCR-ABL, and further research is necessary.
References
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