Abstract
The impact of first-generation covalent KRASG12C inhibitors has been reduced due to the development of drug resistance, tolerability and challenges combining with immunotherapy. We designed olomorasib, a next-generation GDP-binding KRASG12C inhibitor, for nanomolar potency as well as selectivity over wild-type inhibition. In both in vitro and in vivo models of KRASG12C -mutant cancers, olomorasib reduces RAS activity and pERK levels, leading to substantial and significant tumor growth inhibition. Additionally, olomorasib combined with immune checkpoint inhibitors demonstrates greater anti-tumor activity compared to monotherapy. Furthermore, we demonstrate that olomorasib binds tightly to KRASG12C even in the presence of clinically relevant second site mutations, a known mechanism of resistance and limitation to currently approved KRASG12C inhibitors. These findings suggest that olomorasib could be effective for patients with KRASG12C mutant cancers either as monotherapy or in combination with immunotherapy. Olomorasib monotherapy and combination treatments are currently being investigated clinically.
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This study was funded by Eli Lilly and Company. This study was sponsored by Eli Lilly and Company.
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At the time of data collection and experimentation, all authors were employees of Eli Lilly and Company. All authors are current stock shareholders of Eli Lilly and Company.
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Peng, S., Zhang, Y., Lin, X. et al. Characterization of KRASG12C inhibitor olomorasib single-agent and combination with activity in KRASG12C-mutant models. Nat Commun (2026). https://doi.org/10.1038/s41467-026-72650-y
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DOI: https://doi.org/10.1038/s41467-026-72650-y
