Src signaling pathways in prostate cancer

Abstract

Knowledge of the molecular events that contribute to prostate cancer progression has created opportunities to develop novel therapy strategies. It is now well established that c-Src, a non-receptor tyrosine kinase, regulates a complex signaling network that drives the development of castrate-resistance and bone metastases, events that signal the lethal phenotype of advanced disease. Preclinical studies have established a role for c-Src and Src Family Kinases (SFKs) in proliferation, angiogenesis, invasion and bone metabolism, thus implicating Src signaling in both epithelial and stromal mechanisms of disease progression. A number of small molecule inhibitors of SFK now exist, many of which have demonstrated efficacy in preclinical models and several that have been tested in patients with metastatic castrate-resistant prostate cancer. These agents have demonstrated provocative clinic activity, particularly in modulating the bone microenvironment in a therapeutically favorable manner. Here, we review the discovery and basic biology of c-Src and further discuss the role of SFK inhibitors in the treatment of advanced prostate cancer.

Fig. 1

Src Activation. SFKs typically have four domains and their activity is regulated by different conformational states. SFKs are usually held in a “closed”, inactive form and transition to an “open”, active form upon stimulation from both extracellular and intracellular signals. Phosphorylation of Tyrosine 530 is a key molecular event associated with the closed conformation. SFKs are frequently activated when extracellular ligands associated with their cognate receptors. SFKs are also activated by androgen receptor signaling and during mitosis. Phosphorylation of Tyrosine 419 is a key molecular event associated with the open conformation. Activated Src can also activate AR, establishing crosstalk between these two grown promoting pathways

Fig. 2

Activation of SFKs and downstream targets stimulate signaling pathways that contribute to multiple biologic processes involved in prostate cancer progression including survival, proliferation, angiogenesis, and metastases