Blocking K-Ras Interaction With the Plasma Membrane Is a Tractable Therapeutic Approach to Inhibit Oncogenic K-Ras Activity

Abstract

Ras proteins are membrane-bound small GTPases that promote cell proliferation, differentiation, and apoptosis. Consistent with this key regulatory role, activating mutations of Ras are present in ∼19% of new cancer cases in the United States per year. K-Ras is one of the three ubiquitously expressed isoforms in mammalian cells, and oncogenic mutations in this isoform account for ∼75% of Ras-driven cancers. Therefore, pharmacological agents that block oncogenic K-Ras activity would have great clinical utility. Most efforts to block oncogenic Ras activity have focused on Ras downstream effectors, but these inhibitors only show limited clinical benefits in Ras-driven cancers due to the highly divergent signals arising from Ras activation. Currently, four major approaches are being extensively studied to target K-Ras–driven cancers. One strategy is to block K-Ras binding to the plasma membrane (PM) since K-Ras requires the PM binding for its signal transduction. Here, we summarize recently identified molecular mechanisms that regulate K-Ras–PM interaction. Perturbing these mechanisms using pharmacological agents blocks K-Ras–PM binding and inhibits K-Ras signaling and growth of K-Ras–driven cancer cells. Together, these studies propose that blocking K-Ras–PM binding is a tractable strategy for developing anti–K-Ras therapies.