Activation of abl family kinases in solid tumors

Abstract

Although c-Abl and Arg non-receptor tyrosine kinases are well known for driving leukemia development, their role in solid tumors has not been appreciated until recently. Accumulating evidence now indicates that c-Abl and/or Arg are activated in some solid tumor cell lines via unique mechanisms that do not involve gene mutation/translocation, and c-Abl/Arg activation promotes matrix degradation, invasion, proliferation, tumorigenesis, and/or metastasis, depending on the tumor type. However, some data suggest that c-Abl also may suppress invasion, proliferation, and tumorigenesis in certain cell contexts. Thus, c-Abl/Arg may serve as molecular switches that suppress proliferation and invasion in response to some stimuli (e.g., ephrins) or when inactive/regulated, or as promote invasion and proliferation in response to other signals (e.g., activated growth factor receptors, loss of inhibitor expression), which induce sustained activation. Clearly, more data are required to determine the extent and prevalence of c-Abl/Arg activation in primary tumors and during progression, and additional animal studies are needed to substantiate in vitro findings. Furthermore, c-Abl/Arg inhibitors have been used in numerous solid tumor clinical trials; however, none of these trials were restricted to patients whose tumors expressed highly activated c-Abl/Arg (targeted trial). Targeted trials are critical for determining whether c-Abl/Arg inhibitors can be effective treatment options for patients whose tumors are driven by c-Abl/Arg.

Keywords: Arg; c-Abl; solid tumor; tyrosine kinase.

Figure 1.

Activation of c-Abl/Arg in solid tumors. Summary of the signals that induce constitutive activation of cell surface receptors (receptor tyrosine kinases, claudin-1), in a variety of solid tumors, induces constitutive activation of c-Abl/Arg. c-Abl/Arg, in-turn, activate a variety of intracellular signaling pathways, which result in increased survival, proliferation, anchorage-independent growth, migration, matrix degradation, and invasion, processes necessary for tumor growth and/or metastatic progression. Arrow colors indicate proteins that are in the same signaling pathways.