Rapid target engagement of KRAS G12C tricomplex inhibitor RO3903 overcomes resistance and drives durable tumor regression

The clinical durability of first-generation KRAS G12C inhibitors is constrained by resistance mechanisms, primarily the rapid, receptor tyrosine kinase (RTK)-mediated reactivation of KRAS to its drug-insensitive, guanosine triphosphate (GTP)-bound (ON) state. Here, we perform a systematic comparative characterization of clinical and investigational KRAS G12C inhibitors, including Sotorasib, Adagrasib, Divarasib, and Elironrasib, and our structurally optimized tricomplex ON inhibitor, RO7783903 (RO3903). We demonstrate that the covalent tricomplex inhibitors RO3903 and Elironrasib effectively outpace dynamic nucleotide cycling, conferring resilience to potent RTK stimulation and overcoming the secondary KRAS mutations that drive clinical resistance to guanosine diphosphate (GDP)-bound (OFF) state inhibitors. Notably, RO3903 potently inhibits tumor growth in a dose-dependent manner across multiple preclinical models, including an orthotopic intracranial model. Furthermore, RO3903 exhibits synergistic efficacy when combined with inhibitors targeting OFF-state KRAS G12C, YAP-TEAD, EGFR/MET, or FAK, as well as with anti-PD1 antibody and anti-PD1/VEGF bispecific antibody immunotherapies. The high potency, fast target engagement, and brain tumor inhibition of RO3903 position this molecule as a valuable tool reagent and a promising partner for combination strategies to achieve durable tumor regression.