Targeting Ras for Anticancer Drug Discovery

Publisher Summary Several recent research observations have rekindled interest in targeting Ras for cancer treatment. Genome-wide cancer genome studies have revealed that the genes most commonly mutated in cancers were already identified in more systematic studies. Another observation involves the association of KRAS mutations with resistance to treatment with inhibitors of the epidermal growth factor receptor (EGFR). The structural and biochemical distinctions between normal and mutant Ras are well delineated. Approaches for blocking Ras have focused on either inhibition of Ras membrane association or downstream effector signaling. This chapter summarizes the specific targets under evaluation for each of these directions. Cell permeable inhibitors are identified and shown to exhibit target based and anti-tumor activity in cell culture and/or mouse models of cancer. These analyses demonstrate tumor prevention rather than inhibition of an already developed tumor. The study provides an overview of the status of the development of inhibitors of Ras effector signaling. With renewed appreciation and interest in Ras as a therapeutic target for cancer treatment, and with promising leads for indirect approaches for blocking Ras function, there remains strong optimism that anti-Ras therapies will finally reach the clinic.