Sci. Signal., 29 March 2011
When Negative Feedback FailsBcr-Abl is a fusion protein with tyrosine kinase activity that causes some forms of leukemia. Bcr-Abl activates Src family tyrosine kinases (SFKs), but resistance to drugs, such as dasatinib and imatinib, that target Bcr-Abl and SFKs limits their clinical usefulness. With global tyrosine phosphoproteomic analysis in a murine leukemia cell line model, Rubbi et al. identified several negative feedback mechanisms that limited SFK activity and showed that their effectiveness was blunted by Bcr-Abl. Sensitivity of human leukemia cell lines to imatinib correlated with the amount of negative feedback signaling to SFKs. By exploring the mechanisms by which Bcr-Abl overpowered the negative feedback, the authors identified potential therapeutic targets for treating leukemias resistant to Bcr-Abl and SFK inhibitors or that may be combined with these tyrosine kinase inhibitors to prevent the development of resistance.
Citation: L. Rubbi, B. Titz, L. Brown, E. Galvan, E. Komisopoulou, S. S. Chen, T. Low, M. Tahmasian, B. Skaggs, M. Müschen, M. Pellegrini, T. G. Graeber, Global Phosphoproteomics Reveals Crosstalk Between Bcr-Abl and Negative Feedback Mechanisms Controlling Src Signaling. Sci. Signal. 4, ra18 (2011).
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