[SRC kinases in tumor therapy].

Abstract

The proto-oncogene src encodes a nonreceptor tyrosine kinase whose expression and activity are correlated with advanced malignancy and poor prognosis in a variety of human cancers. Nine additional enzymes with homology to src have been identified and collectively are referred to as src family kinases (SFKs). SFKs represent the largest family of nonreceptor tyrosine kinases and interact directly with receptor tyrosine kinases, G-protein-coupled receptors, steroid receptors, signal transducers and activators of transcription, and molecules involved in cell adhesion and migration. These interactions lead to a diverse array of biological functions including proliferation, cell growth, differentiation, cell shape, motility, migration, angiogenesis, and survival. Studies investigating mutational activation of src in human cancers suggest that this may be a rare event and that wild-type src is weakly oncogenic. Thus, the role of src in the development and progression of human cancer remains unclear; however, it has been suggested that SFK activity may be linked to cancer progression and metastatic disease by facilitating the action of other signaling proteins. SFKs may therefore represent a promising therapeutic target. As a consequence, src-targeting therapies are a recent development. Although numerous agents have been discovered, few have reached clinical development. Amongst them, dasatinib, bosutinib and saracatinib are already in phase II testing and data from these trials suggest that these agents are well tolerated, however, they possessed little clinical activity as monotherapy. Future clinical development will therefore include trials of combination therapy.