Targeting signal transduction pathways in colorectal cancer--more than skin deep

Colorectal cancer is the second leading cause of cancer death in the United States. The nihilism that previously often characterized the treatment of patients with this disease has been replaced by a measure of excitement, given recent therapeutic advances. These advances have been stimulated in part through identification of cellular processes characteristic of colorectal cancers that permit therapeutic targeting with favorable therapeutic index. Inhibition of the epidermal growth factor receptor in the clinic has provided proof of principle that interruption of signal transduction cascades in patients with colorectal cancer has therapeutic potential. This experience has also taught us that resistance to such rationally developed targeted therapeutic strategies is common. In this article, we review the role of signal transduction in colorectal cancer, introduce promising molecular targets, and outline therapeutic approaches under development. We will describe the barriers to success, and highlight paradigms to facilitate rapid and successful evaluation of new agents, in a clinical context that has (by virtue of recent clinical successes) become a somewhat crowded playing field.