Tailoring Ras-pathway--inhibitor combinations for cancer therapy.

Constitutive activation of Ras pathways plays a critical role in cancer development and maintenance. Inhibitors of such pathways are already in use for cancer therapy, with significant but as yet only partial success in the most deadly types of human cancers, against which even combinations of Ras-pathway inhibitors with classic cytotoxic drugs or irradiation are insufficient. Combinations of farnesyl transferase inhibitors (FTI's), inhibitors of Ras pathways, are now in use in clinical trials. In this review we analyze possible reasons for the limited efficacy--including the diverse and sometimes even contradictory effects of active Ras pathways in tumor cells--and propose possible alternative methods of tailoring Ras-pathway inhibitor combinations for cancer therapy. Such tailoring is now possible thanks to increased knowledge of the complexity of Ras pathways, their cooperation with other oncogenic pathways, and their "addictive" nature. We provide examples demonstrating that this knowledge can be translated into useful drug combinations that disrupt multiple oncogenic pathways and hit a weak point of a given tumor cell. One such example is combination treatment with a Ras inhibitor and a glycolysis blocker for pancreatic tumor cells. The future design of such potential drug combination therapies and the follow-up of their outcome will undoubtedly be facilitated by gene-expression profiling and proteomic methods.