Daraxonrasib and Beyond: Pan‐RAS Inhibition, Resistance, and Next‐Generation Strategies

Abstract

ABSTRACT RAS proteins have long been considered difficult therapeutic targets, but allele‐selective inhibitors established the clinical tractability of mutant RAS. Daraxonrasib (RMC‐6236), an oral pan‐RAS inhibitor, has now extended this concept by targeting multiple mutant and wild‐type RAS proteins. In the randomized phase III RASolute 302 trial, daraxonrasib substantially improved survival over chemotherapy in previously treated metastatic pancreatic ductal adenocarcinoma while maintaining manageable toxicity, thereby establishing a clinically useful therapeutic window for pan‐RAS inhibition. Nevertheless, epithelial toxicity and acquired resistance, including mutations affecting ternary‐complex formation and mechanisms associated with increased KRAS abundance, remain important challenges. This review discusses the mechanistic and clinical development of daraxonrasib and examines emerging strategies designed to improve the depth, durability, and selectivity of RAS suppression. These include pan‐KRAS inhibitors, targeted RAS degraders, RAS‐cleaving protein biologics, and tumor‐directed delivery systems. Together, these approaches may reshape the treatment of RAS‐driven cancers across tumor types and disease stages.