Pharmacological strategies to target oncogenic KRAS signaling in pancreatic cancer

Abstract

The clear importance of mutated KRAS as a therapeutic target has driven the investigation of multiple approaches to inhibit oncogenic KRAS signaling at different molecular levels. However, no KRAS-targeted therapy has reached the clinic to date, which underlies the intrinsic difficulty in developing effective, direct inhibitors of KRAS. Thus, this article provides an overview of the history and recent progress in the development of pharmacological strategies to target oncogenic KRAS with small molecule agents. Mechanistically, these KRAS-targeted agents can be classified into the following four categories. (1) Small-molecule RAS-binding ligands that prevent RAS activation by binding within or outside the nucleotide-binding motif. (2) Inhibitors of KRAS membrane anchorage. (3) Inhibitors that bind to RAS-binding domains of RAS-effector proteins. (4) Inhibitors of KRAS expression. The advantage and limitation of each type of these anti-KRAS agents are discussed.

Keywords: G-duadruplex; KRAS G12C mutant-specific inhibitors; KRAS membrane anchorage; KRAS post-translational modifications; KRAS-ILK regulatory loop; KRAS-binding ligands; Oncogenic KRAS; Pancreatic cancer; Pharmacological inhibitors; RAS-binding domain inhibitors; RAS-effector interactions; YES-associated protein 1.