Post-translational modifications of KRAS: from molecular regulation to therapeutic targeting

The rat sarcoma virus (RAS) proteins are small GTPases that regulate cell signaling and are frequently mutated in human cancers. Their activity is mainly controlled by cycling between guanosine diphosphate (GDP)-bound and guanosine triphosphate (GTP)-bound states, which is regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). In addition to this classical mechanism, post-translational modifications (PTMs) provide another important layer of RAS regulation. RAS proteins undergo several types of modification, including farnesylation, proteolysis, methylation, palmitoylation, phosphorylation, ubiquitylation, nitrosylation, ADP-ribosylation, and glucosylation. These modifications can influence RAS localization, stability, activity, and interactions with other signaling proteins. As a result, post‑translational modifications can influence the strength, duration and location of RAS signaling, and thereby contribute to tumor development, progression and treatment response. The recent success of direct RAS inhibitors has overturned the long-standing perception of RAS as an undruggable target and has renewed interest in the broader regulatory network that controls RAS function. Enzymes that install, remove or recognize RAS modifications may provide complementary therapeutic opportunities and potential strategies to overcome resistance. In this Review, we discuss the molecular mechanisms and functional consequences of RAS post-translational modifications, their interplay with oncogenic mutations, and emerging therapeutic approaches targeting RAS and its modification-dependent regulatory machinery.