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Genes Cancer. 2012 May;3(5-6):436-46. doi: 10.1177/1947601912458584.

Structure, regulation, signaling, and targeting of abl kinases in cancer.

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1
École polytechnique fédérale de Lausanne (EPFL), School of Life Sciences, Swiss Institute for Experimental Cancer Research (ISREC), Lausanne, Switzerland.

Abstract

Abl kinases are prototypic cytoplasmic tyrosine kinases and are involved in a variety of chromosomal aberrations in different cancers. This causes the expression of Abl fusion proteins, such as Bcr-Abl, that are constitutively activated and drivers of tumorigenesis. Over the past decades, biochemical and functional studies on the molecular mechanisms of Abl regulation have gone hand in hand with progression of our structural understanding of autoinhibited and active Abl conformations. In parallel, Abl oncoproteins have become prime molecular targets for cancer therapy, using adenosine triphosphate (ATP)-competitive kinase inhibitors, such as imatinib. Abl-targeting drugs serve as a paradigm for our understanding of kinase inhibitor action, specificity, and resistance development. In this review article, I will review the molecular mechanisms that are responsible for the regulation of Abl kinase activity and how oncogenic Abl fusions signal. Furthermore, past and ongoing efforts to target Abl oncoproteins using ATP-competitive and allosteric inhibitors, as well as future possibilities using combination therapy, will be discussed.

KEYWORDS:

Bcr-Abl; kinase inhibitor; kinase structure; tyrosine kinase

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