Targeting KRAS mutations: orchestrating cancer evolution and therapeutic challenges

Activating KRAS mutations are highly relevant to various cancers, and KRAS is the most frequently altered oncogenic protein in solid tumors. While historically considered undruggable, two KRAS^G12C inactive state-selective inhibitors are currently approved for treating patients with non-small cell lung cancer. However, these agents only demonstrate a 30-40% response rate and a median progression-free survival of approximately 6 months, with the inevitable emergence of resistance mechanisms, hence remaining far from achieving a cure. Additionally, several cancers with poor prognostic outcomes, such as pancreatic adenocarcinoma, are driven by other non-G12C KRAS mutations and thus have no effective targeted therapies. Improvements in understanding RAS signaling, RNA, and nucleic acid chemistry, as well as the role of the tumor microenvironment, have sparked a paradigm shift in the approach to KRAS inhibition and suggested the potential for several novel combination therapies. In this review, we provide an overview of the RAS pathway and discuss the ongoing development and status of therapeutic strategies for targeting the oncogenic RAS. We further delve into the challenges of resistance mechanisms to better understand the rationale behind these developing strategies, describe their mechanisms of action, and offer insights into the current clinical trial status of each of these approaches.