Ponatinib Inhibition of BCR-ABL

Ponatinib 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. Ponatinib is considered a third generation BCR-ABL inhibitor (Imatinib being the progenitor) due to its effectiveness against the T315I mutation in BCR-ABL. For greater detail of some of the signalling pathways inhibited by BCR-ABL inhibition, refer to the pathway titled BCR-ABL Action in CML Pathogenesis.