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

RO3903, a covalent KRAS G12C tricomplex ON inhibitor, rapidly engages its target and potently inhibits tumor growth dose-dependently across multiple preclinical models, including orthotopic intracranial tumors.

• Why it matters: First-generation KRAS G12C inhibitors face limited clinical durability because RTK signaling rapidly reactivates KRAS to its drug-insensitive ON state, and secondary KRAS mutations drive resistance.
• What they did: The study compared clinical and investigational KRAS G12C inhibitors (Sotorasib, Adagrasib, Divarasib, Elironrasib) and structurally optimized RO7783903 (RO3903), testing whether tricomplex inhibitors outpace dynamic nucleotide cycling under RTK stimulation.
• The result: RO3903 and Elironrasib resist potent RTK stimulation, overcome resistance linked to secondary KRAS mutations against GDP-bound OFF inhibitors, and show synergy with OFF-state KRAS G12C, YAP-TEAD, EGFR/MET, FAK, and anti-PD1-based immunotherapies.

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