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Pathway Description
Imatinib Inhibition of BCR-ABL
Homo sapiens
Drug Action Pathway
Imatinib is a tyrosine kinase inhibitor used to treat cancers such as 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. Imatinib 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. Imatinib resistance in the form of BCR-ABL mutations (e.g. T315I) is an ongoing challenge. Next generation inhibitors have been developed to combat this resistance, but further research is necessary.
References
Imatinib Inhibition of BCR-ABL References
Quintas-Cardama A, Kantarjian H, Cortes J: Flying under the radar: the new wave of BCR-ABL inhibitors. Nat Rev Drug Discov. 2007 Oct;6(10):834-48. doi: 10.1038/nrd2324.
Pubmed: 17853901
O'Hare T, Deininger MW, Eide CA, Clackson T, Druker BJ: Targeting the BCR-ABL signaling pathway in therapy-resistant Philadelphia chromosome-positive leukemia. Clin Cancer Res. 2011 Jan 15;17(2):212-21. doi: 10.1158/1078-0432.CCR-09-3314. Epub 2010 Nov 22.
Pubmed: 21098337
Cilloni D, Saglio G: Molecular pathways: BCR-ABL. Clin Cancer Res. 2012 Feb 15;18(4):930-7. doi: 10.1158/1078-0432.CCR-10-1613. Epub 2011 Dec 8.
Pubmed: 22156549
Thomas J, Wang L, Clark RE, Pirmohamed M: Active transport of imatinib into and out of cells: implications for drug resistance. Blood. 2004 Dec 1;104(12):3739-45. doi: 10.1182/blood-2003-12-4276. Epub 2004 Aug 17.
Pubmed: 15315971
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