Daraxonrasib and the era of pan-RAS inhibition: mechanisms, clinical advances, and resistance landscapes

Activating RAS mutations drive a substantial proportion of human cancers, yet for decades RAS was considered undruggable. The recent development of tri-complex inhibitors (TCIs) such as daraxonrasib (RMC-6236) has transformed the therapeutic landscape by enabling potent, multi-selective targeting of the active, GTP-bound state of multiple RAS isoforms. This review synthesizes preclinical and clinical evidence on daraxonrasib and related RAS(ON) inhibitors across RAS-mutant malignancies, including pancreatic ductal adenocarcinoma, non-small cell lung cancer, colorectal cancer, melanoma, and cholangiocarcinoma. We examine the structural basis of TCI action, pharmacokinetic considerations, and the profound tumor regressions observed in early-phase trials, including the unprecedented overall survival benefit in PDAC. A central focus is the emergence of resistance through diverse mechanisms: acquired mutations in CYPA, RAS, and BRAF that disrupt drug-target complex formation or restore RAS-RAF signaling; adaptive rewiring via mTORC1, STAT3, and cell cycle pathways; and tumor microenvironment-mediated resistance. We further explore rational combination strategies designed to forestall resistance, including vertical MAPK pathway blockade, orthogonal inhibition of EGFR/STAT3, CDK4/6 targeting, and immunotherapy combinations that leverage RAS inhibition-induced immune priming. By integrating structural biology, translational pharmacology, and clinical outcomes, this review provides a comprehensive framework for understanding the promise and challenges of pan-RAS inhibition in precision oncology.