Src A Target For Chronic Myeloid Leukemia Therapy

Src kinases represent a family of nine structurally homologous nonreceptor intracellular tyrosine kinases (Src, Fyn, Yes, Blk, Yrk, Fgr, Hck, Lck, and Lyn) that regulate signal transduction pathways involved in cell growth, differentiation, and survival (4). The expression of some Src kinases is ubiquitous, whereas others display more tissue-specific patterns of expression. For example, Hck, Lyn, Fgr, Lck, and Blk are strictly restricted to hematopoietic cells (4). Furthermore, Hck is circumscribed to myeloid cells and B-lymphocytes, whereas Lyn is expressed in myeloid cells, B-lymphocytes, and NK cells (4). In addition, multiple domains of Bcr-Abl interact with Hck and Lyn leading to their activation, and experiments with Src dominant-negative mutants suggest that Src kinases play a role in proliferation of BCR-ABL-expressing cell lines (4-6). However, neither the formation of the Hck-Bcr-Abl complex nor the Bcr-Abl-mediated activation of Hck is dependent on the Abl kinase activity (7). Overexpression of Src family of kinases has also been implicated in BCR-ABL-mediated leukemogenesis and, in some cases, in imatinib resistance (8-11). Paired samples from patients with CML obtained before and after imatinib failure suggested that overexpression of Hck and Lyn occurred during CML progression to blast phase (BP), suggesting that acquired imatinib resistance may be mediated by overexpression of Src kinases in at least some patients (9). Activation of Src kinases may promote phosphorylation of BCR-ABL and interaction with Grb2 (6,7). In addition, Abl has significant sequence homology with Src and, in its active configuration, it bears a remarkable structural resemblance with Src family kinases. ATP-competitive compounds originally developed as Src inhibitors frequently have potent inhibition of Abl kinase due to the striking resemblance between the catalytically active state of both protein kinases (12). On the basis of the structural similarity between Abl and Src and their proposed critical role in the pathogenesis of CML, it could be hypothesized that small molecule inhibitors with activity against both ABL and Src may have increased activity in CML compared to that of more selective inhibitors, such as imatinib that has negligible activity against Src kinases. This may be at least partially due to the fact that in the inactive configuration, the only one to which imatinib can bind, Abl is much less structurally similar to Src.

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