SRC: a century of science brought to the clinic

Abstract

The SRC family kinases are the largest family of nonreceptor tyrosine kinases and one of the best-studied targets for cancer therapy. SRC, arguably the oldest oncogene, has been implicated in pathways regulating proliferation, angiogenesis, invasion and metastasis, and bone metabolism. More recently, researchers have proposed that the transforming ability of SRC is linked to its ability to activate key signaling molecules in these pathways, rather than through direct activity. It has been hypothesized that blocking SRC activation may inhibit these pathways, resulting in antitumor activity. However, successfully targeting SRC in a clinical setting remains a challenge, and SRC inhibitors have only recently begun to move through clinical development. Preclinical studies have identified specific molecular "subgroups" and histologies that may be more sensitive to SRC inhibition. In addition, other studies have demonstrated synergistic interactions between SRC inhibitors and other targeted therapies and cytotoxics. In this review, we summarize SRC biology and how it has been applied to the clinical development of SRC inhibitors. The status of SRC inhibitors, including dasatinib, saracatinib, and bosutinib, which are in phase 1, 2, and 3 trials, is highlighted.

Figure 1

Methods of SRC activation and inactivation. Phosphorylation of Tyr530 at the C-terminus locks the protein in a closed, inactive conformation stabilized through interactions between the SH3 and kinase domains. Dephosphorylation of Tyr530 and autophosphorylation of Tyr419 within the catalytic domain allow SRC to assume an open, active conformation. SRC activity is also regulated by receptor tyrosine kinases and direct binding of FAK to the SH2 domain.