The SRC family of protein tyrosine kinases: a new and promising target for colorectal cancer therapy

Abstract

Aberrant activation of the Src family of tyrosine kinases has been implicated in the development and progression of colorectal cancer (CRC). As a result, Src inhibitors are now being studied as possible therapeutic agents to treat metastatic disease. In this review, we discuss the effects of aberrant Src activation in CRC, Src as a target of single-agent drug therapy, and Src as a target of combination therapy with epidermal growth factor receptor inhibition and cytotoxic chemotherapy. The greatest potential for clinically relevant benefit most likely lies in combination regimens. Further evaluation with biomarkers will continue to define the molecular phenotype of patients with CRC who will benefit the most from Src-based therapy.

Figure 1. Structure of Src in Its Active Conformation With ATP-Analogue Ligand

Rendered in Cn3D based on a structure from Xu et al. Kopetz, S: Targeting Src and Epidermal Growth Factor Receptor in Colorectal Cancer: Rationale and Progress into the Clinic. Gastrointest Cancer Res 1:S37–S41, 2007. Reprinted with the permission of the International Society of Gastrointestinal Oncology.

Figure 2. Src Plays a Role in Signaling Through a Variety of Membrane-Bound Receptors as Well as in Responding to Intracellular Oxidative Stress

The multiple effectors of Src include the PI3K/Akt, Ras/Raf/MAPK, STAT3/STAT5B, and p130 pathways. Abbreviations: EGFR = epidermal growth factor receptor; MAPK = mitogen-activated protein kinase; PI3K = phosphatidylinositol 3-kinase

Figure 3. Preclinical Evidence and Potential Clinical Benefit From the Various Mechanisms Attributed to Src Inhibition

In colorectal cancer, the greatest benefit will likely be as part of combination therapy as a chemotherapy sensitizer or through antiangiogenic effects. Previously published in Kopetz S, Shah AN, Gallick GE. Src continues aging: current and future clinical directions. Clin Cancer Res 2007; 13:7232-6.