Activating somatic K-Ras mutations are associated with >15% all human tumors and up to 90% of specific tumor types such as pancreatic cancer. Successfully inhibiting abnormal K-Ras signaling would therefore be a game changer in cancer therapy. However, K-Ras has long been considered an undruggable target for various reasons. This view is now changing by the discovery of allosteric inhibitors that directly target K-Ras and inhibit its functions, and by the identification of new mechanisms to dislodge it from the plasma membrane and thereby abrogate its cellular activities. In this review, we will discuss recent progresses and challenges to inhibiting aberrant K-Ras functions by these two approaches. We will also provide a broad overview of other approaches such as inhibition of K-Ras effectors, and offer a brief perspective on the way forward.
Keywords: K-Ras; K-Ras trafficking; cancer; director inhibitors; localization; plasma membrane.