Src-family tyrosine kinases as therapeutic targets in advanced cancer

Abstract

Src-family tyrosine kinases (SFK) play critical roles in mediating many cellular pathways such as proliferation, adhesion, survival, differentiation and cell motility. There is clear evidence that SFK activity is increased in many human cancers, either through gene amplification, transcriptional upregulation, posttranslational modification by activated upstream growth factor receptors, and even in rare cases, by mutations known to increase intrinsic tyrosine kinase activity in oncoviral forms of SFK. Many recent studies using animal models of human cancer seem to indicate that SFK may only be appropriate therapeutic targets in a subset of primary tumors because of the existence of multiple independent pathways that mediate oncogenic signaling. In contrast, SFK seem to be required for specific parameters of malignant progression, such as recurrence and/or metastasis- especially involving growth in the bone microenvironment. The resulting development of SFK antagonists, and their progression through clinical trials, has brought renewed focus on this tyrosine kinase family as critical mediators of the so-called lethal phenotype of cancer.