Abstract
Aberrant activation of members of the Src family of nonreceptor protein tyrosine kinases is common in solid tumor malignancies and may contribute to the development and/or progression of these tumors. As a result, four Src inhibitors are now in more than 50 clinical trials for at least 14 different types of solid tumors. In this review, we briefly discuss the preclinical rationale for Src inhibitors, the development strategies most likely to be successful in the clinic, and the rationale for Src inhibitors in combination with other agents as part of a more comprehensive therapeutic strategy. As the use of Src family inhibitors in clinical trials on solid tumors is in its infancy, further studies on the roles of Src family kinases in tumor progression, chemoresistance, epidermal-to-mesenchymal transition, and other properties of tumor progression will be important in designing the most effective clinical trials using these inhibitors.
Highlights
Aberrant activation of members of the Src family of nonreceptor protein tyrosine kinases is common in solid tumor malignancies and may contribute to the development and/or progression of these tumors
With a maturing understanding of the complexities of Src function and the burgeoning number of Src inhibitors entering the clinic, Src and its family members have come of age as a potential target for cancer therapy
Despite the fact that grade 3 or 4 neutropenia and thrombocytopenia were seen in 45% and 35% of chronic myelogenous leukemia patients, respectively, myelosuppression has not been prominent in studies of dasatinib in patients with solid tumors [21, 22]
Summary
Src: the first oncogene discovered, the first shown to have intrinsic tyrosine kinase activity, and the subject of two Nobel prizes. Many of the concepts of proto-oncogenes and their roles in signal transduction and cancer emanated from studies on Src. until recently, Src was not seriously considered as a target for development of anticancer drugs. With a maturing understanding of the complexities of Src function and the burgeoning number of Src inhibitors entering the clinic, Src and its family members have come of age as a potential target for cancer therapy. Src and Src family kinases cooperate in several cellular processes including migration, adhesion, invasion, angiogenesis, proliferation, differentiation, and immune function This review will touch only briefly on Src functions, focusing instead on the areas of greatest promise and greatest difficulties for moving Src inhibitors from the laboratory to success in the clinic. F 2007 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-07-1902
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