KRAS G12C inhibitor RO3903 suppresses tumor growth in preclinical models, including intracranial

In a study published in Proceedings of the National Academy of Sciences, researchers compared clinical and investigational KRAS G12C inhibitors (Sotorasib, Adagrasib, Divarasib and Elironrasib) with their own structurally optimized tricomplex inhibitor RO7783903 (RO3903) doi.orgProceedings of the National Academy of Sciencesdoi.orgOpen source ↗. The work was preclinical.

According to the authors, the clinical durability of first-generation inhibitors is limited by resistance, primarily rapid receptor tyrosine kinase (RTK)-mediated reactivation of KRAS to the drug-insensitive, GTP-bound (ON) state doi.orgProceedings of the National Academy of Sciencesdoi.orgOpen source ↗. The authors report that the covalent tricomplex inhibitors RO3903 and Elironrasib outpace dynamic nucleotide cycling, remain effective under potent RTK stimulation and overcome secondary KRAS mutations that drive clinical resistance to inhibitors of the GDP-bound (OFF) state doi.orgProceedings of the National Academy of Sciencesdoi.orgOpen source ↗.

RO3903 inhibited tumor growth in a dose-dependent manner across multiple preclinical models, including an orthotopic intracranial model doi.orgProceedings of the National Academy of Sciencesdoi.orgOpen source ↗. It showed synergistic efficacy in combination with inhibitors of OFF-state KRAS G12C, YAP-TEAD, EGFR/MET or FAK, as well as with anti-PD1 antibody and anti-PD1/VEGF bispecific antibody immunotherapies doi.orgProceedings of the National Academy of Sciencesdoi.orgOpen source ↗.

The authors describe RO3903 as a tool reagent and a promising partner for combination strategies aimed at durable tumor regression.