K-Ras

Mutational activations of KRas is one of the most common oncogenic events in human cancers and a heavily pursued target in therapeutic development for decades. Mutant KRas protein engages a host of signaling cascades that culminate in uncontrolled cell proliferation, enhanced survival, and set the stage for acquisition of further genetic events that propel cancer cells towards more malignant phenotypes. Direct targeting of KRas protein with inhibitors that disrupt its maturation and proper trafficking has not been successful in clinic. Instead, much attention is now focused on targeting the effector cascades that mutant KRas utilizes to exert its oncogenic feats, which include the PI3K/AKT/ mTOR and Raf/MEK/ERK cascades. Numerous inhibitors targeting these pathways have been developed and are being tested in clinic. However, durable clinical success will depend on identifying effective combinations with tolerable side effects and strategies to overcome resistance mechanisms.